Reduced Cyclophosphamide Combined with Etoposide and Total Body Irradiation as a Conditioning Regimen for Patients with Impaired Cardiac Function Undergoing Allogeneic Stem Cell Transplantation.
Authors: Yoshimi Akihide , Nannya Yasuhito , Oshima Kumi , Sakata-Yanagimoto Mamiko , Takahashi Tsuyoshi , Kanda Yoshinobu , Motokura Toru , Chiba Shigeru , Kurokawa Mineo 
Published: April 2020

Abstract
Cardiac toxicity due to conditioning regimens is a critical problem in the hematopoietic stem cell transplantation (HSCT). High-dose cyclophosphamide, which is a major component of conventional myeloablative regimens, is considered to be a main cause of cardiac toxicity. Although reduced intensity conditioning regimens have been developed in order to diminish regimen related toxicities for patients with pre-transplant co-morbidity, their anti-neoplastic effects have been revealed to be insufficient especially for patients with acute lymphoblastic leukemia. Therefore, it is imperative to establish an alternative preparative regimen with myeloablative intensity for patients with impaired pre-transplant cardiac function. From June 1995 at the University of Tokyo, we have adopted a heart protective regimen (VP/rCY/TBI) which is composed of continuous infusion of VP-16 20 mg/kg for 2 days, CY 40 mg/kg for 1 day, and 12 Gy of fractionated total body irradiation (TBI) for 17 patients because they had impaired cardiac function defined by ejection fraction (EF) less than 0.55 (n=15) or a history of congestive heart failure (n=1) or pulmonary hypertension (n=1). The clinical relevance of VP/rCY/TBI regimen was evaluated by retrospectively comparing the outcome of VP/rCY/TBI recipients with that of conventional CY/TBI (CY 60 mg/kg for 2 days + fractionated TBI 12 Gy, which was administered to 140 patients during the same period) recipients. The characteristics analysis revealed that VP/rCY/TBI recipients had higher cumulative doses of anthracyclines (354 mg/m2 vs 150 mg/m2 calculated as the equivalence of native doxorubicin, p&lt;0.0001), lower EF (0.51 vs 0.66, p=0.005), larger left ventricular end-systolic dimension (LVDs) (35 mm vs 30 mm, p&lt;0.0001), and worse Karnofsky performance scales (KPS) (90 vs 100, p=0.0037) than CY/TBI recipients. There was no difference in the other characteristics between the two groups, including age, disease status, ferritin level, and the other UCG findings. The median follow up period for surviving patients was 43.9 months after transplantation (range: 4–146 months). Survival analysis was conducted considering non-relapse mortality (NRM) and relapse rates as competing risk factors of each other. The relapse rate was not significantly different between the two groups (p=0.24), which indicates that VP/rCY/TBI regimen has a comparable anti-tumor effect to standard CY/TBI regimen. In addition, despite poorer KPS and more cardiac co-morbidity in the VP/rCY/TBI arm, no difference in the NRM rates was observed between the two groups. Especially, it is noteworthy that Bearman grade III-IV cardiac toxicity within 28 days after HSCT was not significantly increased in VP/rCY/TBI group (one in VP/rCY/TBI recipients (5.9%) and five in CY/TBI recipients (3.6%), p=0.64). There was no significant difference in the incidence of grade II-IV (p=0.35) or grade III-IV (p=0.10) acute GVHD. From these results, we conclude that VP/rCY/TBI regimen can be safely administered for patients with pre-transplant cardiac co-morbidity while preserving anti-neoplastic effects.