title: Cardiac toxicity of high-dose cyclophosphamide in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation.
abstract: High-dose cyclophosphamide is a well-known mobilization regimen in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Highly differing rates of cardiac complications associated with high-dose cyclophosphamide have been reported. To date, no systematic clinical study has investigated high-dose cyclophosphamide mobilization regimens in multiple myeloma patients and evaluated its cardiotoxicity. We administered high-dose cyclophosphamide (4 g/m2) to 23 consecutive multiple myeloma patients and followed the patients for 15 days by serially measuring the cardiotoxicity biomarkers troponin I (TnI), brain natriuretic peptide (BNP), and endothelin 1 (ET-1). Systolic and diastolic left ventricular function was assessed by complete echocardiography before and at 6 to 8 weeks after the therapy. Patients younger than 55 years showed significant differences between basal TnI levels and TnI concentrations determined at 15 days after high-dose cyclophosphamide treatment (P = .028). Significant differences between basal BNP concentrations and BNP levels measured at 8 hours after high-dose cyclophosphamide treatment were found in the entire group of patients as well as in 2 subgroups, patients younger than 55 years and those older than 55 years (P <.0001, P <.001, and P = .001, respectively). ET-1 results for the entire group of patients showed a significant difference between baseline ET-1 values and ET-1 values determined 8 hours after high-dose cyclophosphamide administration (P = .004). Echocardiographic measurements revealed a barely nonsignificant decrease in cardiac output after high-dose cyclophosphamide infusion compared with pretreatment values (P = .06), a result in accord with echocardiographically detected increases in mild functional mitral regurgitation (P = .025). TnI levels at 15 days after the completion of treatment correlated with left ventricular diastolic dysfunction, as indicated by the s/d index (r = 0.61; P = .04). In conclusion, the significant neurohumoral activation of heart failure occurring after high-dose cyclophosphamide treatment is manifested by an increase in BNP and ET-1 levels, yet without concomitant cardiomyocyte necrosis. BNP levels and to a lesser extent ET-1 levels are much more sensitive indicators of myocardial injury than functional tests, such as echocardiography, whereas diastolic functional parameters are more sensitive predictors of early cyclophosphamide-induced cardiotoxicity. Mild functional mitral regurgitation may develop in patients given high-dose cyclophosphamide therapy.
authors.affiliation: Department of Hematology, University Clinical Center Ljubljana, Ljubljana, Slovenija. samo.zver@kclj.si
authors.forename: Samo
authors.initials: S
authors.lastname: Zver
authors.forename: Vesna
authors.initials: V
authors.lastname: Zadnik
authors.forename: Matjaz
authors.initials: M
authors.lastname: Bunc
authors.forename: Polona
authors.initials: P
authors.lastname: Rogel
authors.forename: Peter
authors.initials: P
authors.lastname: Cernelc
authors.forename: Mirta
authors.initials: M
authors.lastname: Kozelj
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D003971:Diastole; D004452:Echocardiography; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy; D006333:Heart Failure / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D014182:Transplantation, Autologous; D019210:Troponin I / Q000097:blood
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D019210:Troponin I; D020097:Natriuretic Peptide, Brain; D003520:Cyclophosphamide