Frequent but Reversible and Manageable Cardiac Complications after Successful Haploidentical HLA-Mismatched Hematopoietic Stem Cell Transplantation (HSCT) without Ex Vivo Graft Manipulation.
Authors: Oshima Kumi , Kanda Yoshinobu , Sakata-Yanagimoto Mamiko , Asano-Mori Yuki , Izutsu Koji , Ogawa Seishi , Motokura Toru , Chiba Shigeru , Hirai Hisamaru 
Published: October 2019

Abstract
Alemtuzumab, a humanized monoclonal antibody directed against human CD52, has a strong lympholytic effect. We performed a study to evaluate the safety of unmanipulated HSCT from 2 or 3 loci-mismatched related donors using in vivo alemtuzumab. A total body irradiation-based regimen was used in young patients, while those 50 years old or older received fludarabine-based but myeloablative conditioning. Alemtuzumab was added to these regimens by intravenous infusion at 0.2 mg/kg/day for 6 days (days −8 to −3). We have treated 14 patients thus far. All achieved neutrophil engraftment with complete donor-type chimerism. Only 1 developed grade III-IV acute GVHD. There was no infection-related death. However, 8 patients (57.1%) developed grade II-III cardiac complications, mainly with congestion, according to Bearman’s criteria. We thus retrospectively analyzed the records of 143 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. On univariate analyses, the cumulative dose of anthracyclines (P=0.001), smoking history (P=0.036), serum ferritin level (P=0.033), left ventricular ejection fraction (P=0.070), HLA-mismatch (P=0.054), and the use of in vivo alemtuzumab (P=0.0002) affected the incidence of grade II to IV cardiac complications with at least borderline significance. Of these, multivariate analysis with backward stepwise selection revealed that the cumulative dose of anthracyclines and the use of in vivo alemtuzumab were independent significant risk factors for cardiac complications (P=0.0016 and P=0.0001, respectively). The duration from transplantation to the onset of cardiac complications was significantly longer in the alemtuzumab group (P=0.02). Fortunately, all the cardiac complications in the alemtuzumab group were successfully treated by the use of diuretics and/or catecholamines. In conclusion, in vivo alemtuzumab has an excellent efficacy to prevent severe GVHD even in HLA-mismatched HSCT. However, the use of in vivo alemtuzumab along with myeloablative conditioning for HLA-mismatched transplantation may affect the incidence of cardiac complications after transplantation. Considering the low incidence of cardiac complications in HLA-matched HSCT with reduced-intensity conditioning, frequent cardiac complications in our series might have resulted not only from alemtuzumab but also from intensive conditioning and/or cytokines excretion associated with the engraftment of HLA-mismatched donor cells. Close monitoring of the cardiac function may be important in such transplantation, especially in patients who had received a high cumulative dose of anthracyclines, because cardiac dysfunction could be manageable by an early detection and early treatment.