Hematopoietic Growth Factors for Primary CNS Lymphoma
Growth factor support with G-CSF (filgrastim) or pegfilgrastim should be strongly considered for patients receiving high-dose methotrexate and high-dose cytarabine regimens for primary CNS lymphoma to maintain dose intensity and prevent febrile neutropenia. 1, 2
Growth Factor Recommendations
When to Use G-CSF
- Primary prophylaxis is appropriate for regimens containing high-dose methotrexate and high-dose cytarabine, as these combinations carry significant risk of grade 3-4 neutropenia (92% in clinical trials) 3, 4
- The European Society for Medical Oncology specifically recommends growth factor support to maintain dose intensity in CNS lymphoma treatment 2
- Dose reductions should be avoided as they compromise outcomes, making prophylactic G-CSF critical 2
Dosing and Administration
- Filgrastim: 5 µg/kg/day subcutaneously starting 24-72 hours after the last day of chemotherapy until adequate neutrophil recovery (ANC >1.0 × 10⁹/L is sufficient; targeting >10 × 10⁹/L is unnecessary) 1
- Pegfilgrastim: Single subcutaneous dose of 6 mg (or 100 µg/kg if individualized) given 24-72 hours after chemotherapy completion 1
- Continue until stable post-nadir ANC recovery 1
Critical Contraindications
- Never administer G-CSF during concurrent chest radiotherapy due to increased complications and mortality risk 1
- Avoid giving growth factors immediately before or simultaneously with chemotherapy due to severe thrombocytopenia risk 1
Adverse Effects to Monitor
High-Dose Methotrexate Toxicities
Renal Toxicity (Most Critical)
- Acute kidney injury from methotrexate precipitation in renal tubules 3, 4
- Monitor for decreased urine output, rising creatinine
- Delayed methotrexate clearance leads to prolonged toxicity
Hepatotoxicity
Mucositis
Myelosuppression
Neurotoxicity
- Acute: confusion, seizures, stroke-like syndrome 3
- Subacute: leukoencephalopathy (rare with modern protocols)
High-Dose Cytarabine Toxicities
Cerebellar Toxicity (Most Serious)
- Irreversible cerebellar syndrome with ataxia, dysarthria, nystagmus 3, 4
- Risk increases with age >50 years, renal dysfunction, cumulative dose
- Perform neurological examination before each cycle focusing on cerebellar function
Ocular Toxicity
- Conjunctivitis, keratitis 3
- Prophylactic steroid eye drops recommended
Severe Myelosuppression
- Grade 4 hematological toxicity in 92% of patients receiving methotrexate plus cytarabine 3
- More profound than methotrexate alone
Gastrointestinal Toxicity
Dermatologic
- Palmar-plantar erythrodysesthesia, rash 3
Rituximab Toxicities
Infusion Reactions (Most Common)
- Fever, chills, rigors, hypotension during or within 24 hours of infusion 5
- Most common with first infusion
- Premedicate with acetaminophen and antihistamine
Hepatitis B Reactivation (Most Dangerous)
- Can be fatal - mandatory screening before treatment 1
- Monitor patients with positive hepatitis B serology throughout treatment
Infections
- Increased risk of bacterial, fungal, and viral infections 5
- Progressive multifocal leukoencephalopathy (PML) reported rarely
Tumor Lysis Syndrome
- Particularly relevant in CNS lymphoma with high tumor burden 2
- Prophylaxis essential (see below)
Cytopenias
- Can cause or worsen neutropenia, thrombocytopenia 5
Cardiac Toxicity
- Arrhythmias, angina during infusion (rare) 5
Combined Regimen Toxicity Profile
The MATRix regimen (methotrexate-cytarabine-rituximab-thiotepa) demonstrates:
- Grade 4 hematological toxicity in majority of patients 4
- Treatment-related mortality of 6% in clinical trials 4
- Febrile neutropenia and infections are most common serious complications 4
- Infective complications occur despite growth factor support 4
Laboratory Monitoring Protocol
Before Initiating Chemotherapy
Mandatory Baseline Labs
Complete Blood Count with Differential
- Establish baseline ANC, hemoglobin, platelets 1
- Ensure ANC >1.5 × 10⁹/L, platelets >100 × 10⁹/L before starting
Comprehensive Metabolic Panel
- Creatinine and calculated GFR (critical for methotrexate dosing and clearance) 3, 4
- Electrolytes (sodium, potassium, bicarbonate)
- Liver function tests (AST, ALT, alkaline phosphatase, bilirubin, albumin)
Hepatitis Screening
- Hepatitis B surface antigen and core antibody (mandatory before rituximab) 1
- If positive or risk factors present: add hepatitis B e-antigen and viral load, consult gastroenterology 1
- Hepatitis C antibody
Cardiac Assessment
- Baseline echocardiogram or MUGA scan if anthracyclines were considered 1
Lactate Dehydrogenase (LDH)
- Prognostic marker; elevated LDH associated with poorer outcomes 6
- Baseline for tumor lysis syndrome monitoring
HIV Testing
- CNS lymphoma has different biology in HIV-positive patients 1
During Each Chemotherapy Cycle
Pre-Chemotherapy (Before Each Cycle)
Complete Blood Count
- Ensure adequate recovery: ANC >1.0-1.5 × 10⁹/L, platelets >75-100 × 10⁹/L 3, 4
- Assess need for dose modifications or delays
Renal Function
- Creatinine and GFR before every methotrexate dose 3, 4
- Methotrexate contraindicated if GFR <60 mL/min (relative); adjust hydration if GFR 60-90 mL/min
Liver Function Tests
- AST, ALT, bilirubin before each cycle 3, 4
- Hold methotrexate if bilirubin >1.5× upper limit normal or transaminases >3× upper limit normal
Electrolytes
- Particularly important for maintaining alkaline urine during methotrexate administration 3
During Methotrexate Administration
Methotrexate Levels
- Measure serum methotrexate at 24,48, and 72 hours post-infusion 3, 4
- Target: <0.1 µmol/L at 72 hours
- Continue leucovorin rescue until methotrexate <0.05 µmol/L
Daily Monitoring During Methotrexate Clearance
- Daily creatinine until methotrexate cleared 3
- Daily electrolytes
- Urine pH (maintain >7.0 with bicarbonate) 3
- Urine output (maintain >100 mL/hour with aggressive hydration)
Post-Chemotherapy Monitoring
Complete Blood Count
- Monitor 2-3 times weekly during nadir period (days 7-21) 3, 4
- Daily if febrile neutropenia develops
- Assess need for transfusion support or G-CSF
Infection Surveillance
- Temperature monitoring
- Clinical assessment for mucositis, pneumonia, catheter infections
Cycle-to-Cycle Assessments
Before Each Subsequent Cycle
- Repeat all baseline labs 1
- Neurological examination focusing on cerebellar function (before each cytarabine dose) 3
- Ophthalmologic assessment if ocular symptoms develop
Response Assessment
Special Monitoring Considerations
Tumor Lysis Syndrome Prophylaxis
- Mandatory given high tumor burden in CNS lymphoma 2
- Allopurinol or rasburicase before first cycle
- Monitor: potassium, phosphate, calcium, uric acid, LDH daily for first 3-5 days 2
Growth Factor Monitoring
- If using G-CSF, check CBC twice weekly during administration 1
- Discontinue when ANC recovers to >1.0 × 10⁹/L 1
Hepatitis B Reactivation Monitoring
- For patients with positive hepatitis B serology: monitor HBV DNA every 1-3 months during and for 6-12 months after rituximab 1
Critical Pitfalls to Avoid
- Never delay methotrexate level monitoring - delayed clearance requires extended leucovorin rescue to prevent fatal toxicity 3
- Never omit pre-chemotherapy renal function assessment - impaired clearance dramatically increases methotrexate toxicity 3, 4
- Never skip hepatitis B screening before rituximab - reactivation can be fatal 1
- Never reduce chemotherapy doses without compelling reason - dose intensity is critical for CNS lymphoma outcomes 2
- Never administer pegfilgrastim to patients who develop febrile neutropenia while on it - use filgrastim or sargramostim instead for therapeutic use 1