Thiotepa-associated cardiomyopathy during blood or marrow transplantation: Association with the female sex and cardiac risk factors

Abstract

Thiotepa (TT) has not been reported to cause cardiomyopathy, whereas cyclophosphamide (Cy)-related cardiomyopathy is well characterized. To search for cases of acute onset cardiomyopathy associated with TT, we retrospectively reviewed 171 patients who received TT-containing conditioning regimens for blood or marrow transplantation (BMT). Nine of 171 patients (5.3%) developed clinical congestive heart failure in the post-BMT period. The median time to onset of heart failure was 15 days after BMT (range 5-30). The median pre-BMT left ventricular ejection fraction (LVEF) was 50% (range 42-65%) as determined by two-dimensional echocardiogram, or gated blood pool scan. At the time of cardiomyopathy onset, LVEF was 30%. Six patients died of causes unrelated to heart failure. All affected patients who developed congestive heart failure following administration of TT had some evidence of cardiac dysfunction prior to transplantation. Significant risk factors for the development of cardiomyopathy included low pre-BMT-LVEF and female sex--particularly in females receiving allogeneic transplantation. The incidence of congestive heart failure with TT-containing regimens was similar to the incidence using other regimens with and without Cy. The mean time to clinical evidence of TT-associated cardiomyopathy was longer than the mean time reported with Cy. We recommend caution in using high-dose TT-containing regimens for patients with histories of cardiac dysfunction.

Cardiac toxicity of high-dose chemotherapy

“…HD thiotepa has been associated with a 5% cardiac toxicity in two studies, 54,55 while other series did not confirm these findings. 8,25 HD ifosfamide cardiotoxicity is reported in only two studies more than 20 years old.…”

“…17,28,79,80,100,104,105 One of these studies also showed that measurement of cardiac reserve during exercise could not predict cardiac morbidity or mortality. 104 On the other hand, three studies reported a significant association between pre-transplant LVEF and cardiotoxicity 18,54,77 and two more described a trend in the same direction. 76,101 However, measurement of LVEF before HD chemotherapy is of limited practical value: increased rates of minor cardiac events, rather than increased mortality due to severe cardiac toxicity, were recorded among patients with diminished (ie 50-54%) baseline LVEF, and 2/3 major cardiac events occurred in patients with normal LVEF.…”

Cardiac toxicity of trastuzumab in metastatic breast cancer patients previously treated with high-dose chemotherapy: a retrospective study

“…Several studies failed to demonstrated a relationship between previous anthracycline exposure and development of cardiac toxicity following high-dose chemotherapy (Nieto et al, 2000;Petros et al, 2002). However, we and others have reported that high-dose alkylating agents in metastatic breast cancer patients previously exposed to cumulative dose of epirubicin X450 mg m À2 is associated with a 4 -5% of congestive heart failure rate (Alidina et al, 1999;Gennari et al, 1999;Bengala et al, 2001). Moreover, we have shown that a double course of high-dose chemotherapy after anthracycline-containing regimen in patients of metastatic breast cancer can induce a transient decline of LVEF to less than 50% in 14.3% of the patients (Bengala et al, 2003).…”

Muromonab-CD3 (Orthoclone OKT3®), methylprednisolone and cyclosporine for acute graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation

“…9 Five patients were treated with thiotepa (Tt) and 1000 cGy TBI. 10 Busulfan (Bu) 16 mg/kg and Cy 120 mg/m 2 (BuCy) conditioning was used in two patients. 11 Two patients received fludarabine (Flu) 125 mg/m 2 plus melphalan (M) 140 mg/m 2 .…”