Adverse Effects of Cyclophosphamide
Cyclophosphamide has significant adverse effects including myelosuppression, hemorrhagic cystitis, gonadal toxicity, secondary malignancies, and various organ toxicities that require careful monitoring and preventive measures. 1
Hematologic and Immunologic Effects
- Myelosuppression is a dose-limiting toxicity, with neutropenia being particularly important as it correlates with increased infection risk 1
- Immunosuppression increases susceptibility to bacterial, fungal, viral, and protozoal infections, including reactivation of latent infections 1
- Pneumocystis jirovecii pneumonia is a significant risk, requiring prophylaxis with trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) 2
- Sepsis and septic shock can occur as complications of severe immunosuppression 1
Urinary Tract Toxicity
- Hemorrhagic cystitis occurs in 2-40% of patients due to the toxic metabolite acrolein 3, 4
- Risk factors include higher cumulative doses, oral administration, and inadequate hydration 4
- Preventive measures include:
- Long-term bladder complications include bladder fibrosis and increased risk of bladder cancer 6
Secondary Malignancies
- Bladder cancer risk is dose-dependent with a 4.5-fold increased risk overall 6
- Risk increases significantly with cumulative doses: 6-fold risk at 20-49g and 14.5-fold risk at ≥50g 6
- Other reported malignancies include acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, and various solid tumors 1
- The risk of secondary malignancies persists for years after discontinuation of therapy 6
Gonadal Toxicity and Fertility
- Amenorrhea occurs in 20-85% of menstruating women, with risk increasing with age and cumulative dose 2, 7
- Azoospermia is common in men, with similar dose and age dependencies 2
- Fertility preservation should be considered before initiating therapy, especially in younger patients 7
- The Euro-Lupus cyclophosphamide regimen (total dose: 3 grams) carries a lower risk of infertility than oral or NIH regimens 7
Cardiovascular Effects
- Cardiotoxicity includes cardiomyopathy, myocarditis, pericarditis, and various arrhythmias 1
- Cardiac failure with fatal outcomes has been reported 1
- At high doses used in bone marrow transplantation, cardiac toxicity becomes dose-limiting 8
Gastrointestinal Effects
- Nausea and vomiting are common during therapy 1
- Less frequent effects include anorexia, abdominal discomfort, diarrhea, and oral mucosal ulceration 1
- Rare but serious complications include hemorrhagic colitis, acute pancreatitis, and hepatotoxicity 1
Pulmonary Toxicity
- Pulmonary toxicity can manifest as pneumonitis, pulmonary fibrosis, or interstitial lung disease 1
- These complications may develop during treatment or appear months after discontinuation 1
Hepatic Effects
- Veno-occlusive liver disease is a rare but serious complication 1
- Other hepatic effects include cholestatic hepatitis, cytolytic hepatitis, and hepatotoxicity with potential hepatic failure 1
Administration and Monitoring Recommendations
- Cyclophosphamide can be administered orally (1-3 mg/kg/day) or intravenously (15 mg/kg every 2-4 weeks) 2
- Regular monitoring should include:
- Intravenous pulse therapy generally results in lower cumulative doses than daily oral therapy 7
- The CYCLOPS study showed that while IV cyclophosphamide caused less leukopenia, it was associated with higher relapse rates compared to oral administration 7
Special Considerations
- In patients with ANCA-associated vasculitis who remain on dialysis without extrarenal manifestations, immunosuppression should be discontinued after 3-6 months to reduce infection risk 7
- Patients with lupus nephritis receiving cyclophosphamide should be counseled about infertility risks, with shared decision-making guiding therapy and interventions 7
- The cumulative dose should be limited to what is required to achieve therapeutic endpoints, given the strong dose-response relationship for adverse effects 6, 9