Emergent Substitution of Fludarabine for Cyclophosphamide Due to Acute Cardiac Toxicity during Conditioning with Successful Engraftment

Cyclophosphamide (CY) is an alkylating agent with potent antineoplastic, immunosuppressive, and immunomodulatory properties. CY induced cardiac toxicity has been documented with higher doses, including cardiomyopathy and hemorrhagic myocarditis. We present 2 cases of successful engraftment after emergent substitution of fludarabine (FLU) for CY due to acute cardiac toxicity. Case 1 is a 6 mo old female with 11q23+ AML who underwent MRD BMT in CR1 with a planned preparative regimen of BU/CY.  BU administration was completed with targeted PKs; however, screening creatine kinase prior to scheduled CY administration on day -5 showed a markedly elevated level of 301 IU/dl with a normal EKG. Troponin1 level was also very elevated at 0.49 ng/ml. Fludarabine (FLU) was substituted for CY at 1.3mg/kg/dose from day -5 through day -2. Neutrophil and platelet engraftment occurred on day +11 and she remains 99% donor 3 yrs post-BMT. Case 2 is a 3 yr-old female with primary myelofibrosis who underwent a 10/10 MUD HSCT with a planned preparatory regimen of CY/TBI.  She received one dose of CY at 60 mg/kg but developed low voltage on her screening EKG prior to the second dose. CK was normal. FLU was substituted for the remaining dose of CY at 30 mg/m2/dose and she received the planned 1200 cGy TBI. She had neutrophil engraftment on day +32 and platelet engraftment on day +96. She remained 100% donor but unfortunately died 10 months post-BMT due to GVHD. Both patients had no further cardiovascular toxicity other than hypertension. CY induced hemorrhagic myocarditis is invariably fatal. Screening tests with serum CK and EKG may be used to predict early signs of cardiac toxicity. In the acute setting of cardiac toxicity, FLU offers an appropriate therapeutic substitution to avoid further cardiac toxicity and allow successful engraftment.