What are the major toxicities of cyclophosphamide? What can be done to prevent them?
• Bone marrow suppression: the WBC nadir after a dose is 8 to 14 days later. Start at 50 mg/day orally with slow escalation and close monitoring.
• Infection (all types, especially herpes viruses): screen for hepatitis B and C, human immunodeficiency virus, and tuberculosis prior to therapy. Keep WBC nadir >3000/mm 3 and preferably >4000/mm 3 . Decrease prednisone dose to <20 to 25 mg/day as soon as possible. Prophylaxis for P. jirovecci pneumonia with Bactrim/Septra, dapsone, or inhaled pentamidine. Pneumococcal and influenza vaccines should be administered.
• Hemorrhagic cystitis and bladder cancer: hemorrhagic cystitis more common in patients with BK virus. Nonglomerular hematuria occurs in up to 50% of patients with 5% developing bladder cancer (31-fold increased risk). Decrease risk by using monthly IV pulse therapy instead of daily oral therapy. Can also use mesna, which is a sulfhydryl compound that binds and inactivates acrolein in the urine. Cigarette smoking increases the risk of bladder toxicity. With daily oral therapy, cyclophosphamide should be dosed in the morning, and patients should ensure adequate hydration (>2 L/day), and empty bladder frequently.
• Malignancy: risk increased two- to four-fold. Increased risk if given daily oral versus monthly IV; the higher the cumulative dose, the greater the risk (50% in patients receiving ≥80 g total dose develop a malignancy).
• Infertility: the risk for ovarian failure ranges from 30% to 70% and varies depending on the patients’ age and cumulative dose. Risk may be two times less with monthly IV than with daily oral dosing. Women aged <20 years have a 13% risk, 20 to 30 years 50% risk, and >30 years 100% risk of premature ovarian failure. Ovarian failure is unlikely if women receive less than 6 monthly doses and common if they receive over 15 monthly pulses (50% with 8 g/m 2 and 90% with 12 g/m 2 ). It is rare in patients who received the Euro-lupus protocol (500 mg IV every 2 weeks × 6 doses). Azoospermia is found in 50% to 90% of men. Various strategies have been tried to limit this toxicity. Banking ova and sperm can be done but is expensive. In women, using gonadotropin-releasing hormone analog (Lupron depot, 3.75 mg intramuscular [IM] monthly or 11.25 mg IM every 3 months plus estradiol 0.3 mg/day [or biweekly patch if patient hypercoagulable]) to reduce hot flashes and protect the bone may be protective. In men, testosterone 100 mg IM every 15 days may be protective. Antimullerian hormone levels are a good marker of ovarian reserve and can be measured at any time during the cycle.
• Pulmonary: less than 1% patients get pneumonitis or pulmonary fibrosis.
• Others: reversible alopecia, syndrome of inappropriate antidiuretic hormone secretion, nausea (use antiemetics), teratogenicity, and reversible posterior leukoencephalopathy syndrome after IV administration.