Cyclophosphamide

  • Derivative of nitrogen mustard
  • High bioavailability ∼75%
  • Peak plasma levels 1-2 hours
  • Hepatic metabolism via cytochrome P450 (CYP450)
  • ½ life 5-9 hours
  • Active metabolites excreted via kidneys
  • Pregnancy Category D

  • Oral or intravenous

Dose

  • 1-3 mg/kg/day 

Or 

  • Monthly pulses 0.5-1g/m2 (less side effect than oral daily dose)
  • – To decrease bladder toxicity, vigorous hydration 24 hours prior to & continuous throughout dosing

  • In general, exert their effect by direct damage to deoxyribonucleic acid (DNA) via cell cycle independent physicochemical interactions (e.g. alkylation, cross-linking, carbamylation)
  • Cyclophosphamide (prodrug) converted by liver to 4-hydroxycyclophosphamide + aldophosphamide, both diffuse into cells & are not directly cytotoxic. Aldophosphamide then cleaved intracellularly to phosphoramide mustard (active metabolite/cytotoxic) + acrolein (highly reactive; cystitis)
  • Cytotoxic metabolites, despite acting independently of cell cycle, preferentially affect proliferating cells 🡪 induce DNA apoptosis & mutagenesis via cross-linking DNA, abnormal base-pair formation, depurination, & chain scission (Effect on B cells > T cells)

FDA (food & drug administration)

  • Mycosis fungoides & advanced cutaneous T cell lymphoma

Off label

  • Bullous disorders (pemphigus, ocular mucous membrane pemphigus)
  • Vasculitides (granulomatosis with Polyangitis, eosinophilic granulomatosis with polyangitis (EGPA), microscopic polyangitis, leukocytoclastic vasculitis)
  • Neutrophilic dermatoses
  • Autoimmune connective tissue disease (AI-CTD)

Absolute

  • Hypersensitivity (cross reaction with Chlorambucil & nitrogen mustard) 
  • Decreased bone marrow function 
  • History of bladder cancer
  • Pregnancy 
  • Lactation

Relative

  • History of lymphoproliferative disease
  • Active infection
  • Hepatic disease
  • Renal disease

  • Hemorrhagic cystitis/ bladder cancer
  • Carcinogenicity (non-Hodgkin lymphoma, leukemia, squamous cell carcinoma) higher risk with transplant/oncology patients
  • Gastrointestinal: anorexia, nausea, vomiting, diarrhea
  • Liver
  • Hematologic 
  • Reproductive: amenorrhea, azoospermia, ovarian failure (risk partially ↓ with Lupron), teratogenicity
  • Dermatologic: Alopecia, pigmentation skin/nails, pigmented band on teeth, urticarial/bullous eruptions, toxic erythema of chemotherapy

Increased levels & toxicity

  • Allopurinol, azoles, quinolones, cimetidine, chloramphenicol
  • Additive toxicities with other immunosuppressants

↓ levels 

  • Barbiturates, phenytoin

Baseline

  • Complete blood count, chemistry profile, liver function tests, urinalysis, pregnancy test (women), contraception
  • Consider ova/sperm harvesting

Follow up

  • Complete blood count, urinalysis weekly x 2-3 months, then every 2weeks x 2-3 months, then monthly if stabilized
  • Chemistry profile, liver function tests monthly x 3-6 months then every 3-6 months
  • Biannual physical exam
  • Annual urine cytology if history of cystitis or if cumulative dose of cyclophosphamide >50g
  • Discontinue if white blood cells <4; Platelets <100 or hematuria

Note

To prevent hemorrhagic cystitis/ bladder cancer: Mesna (oral or intravenous) & good hydration; especially consider in patients taking oral cyclophosphamide for prolonged periods/higher dose