Mitoxantrone-related acute leukemia in MS

Abstract

Despite the long-standing and extensive use of mitoxantrone (MTZ) for the treatment of aggressive forms of multiple sclerosis (MS), especially in Europe, its benefit-risk profile remains controversial. In particular, the risk of developing therapy-related acute leukemia (TRAL) and cardiotoxicity have led to treatment restrictions for MTZ; however, the precise risk for these severe complications is still unclear. Here we review current data on TRAL incidence, research strategies aimed at individual risk stratification, and provide recommendations for hematologic monitoring. A recent meta-analysis indicates a TRAL risk of approximately 0.81%, more than 10-fold higher than in previously reported meta-analyses (0.07%). There also appear to be considerable differences among countries, with recent TRAL risk estimates from Italy as high as 0.93%, compared to the 0.25%-0.41% risk reported from Germany and France. Whereas methodologic differences may partly account for some of these differences, high regional variability may point to exogenous factors such as heterogeneous treatment protocols and cotreatments. In addition, genetic risk factors (MTZ metabolism, DNA repair) might contribute to the individual risk profile. The case of potentially curable MTZ-induced secondary leukemia highlights the need for close hematologic monitoring during and after therapy. Intensive collaboration between neurologists and hematologists will likely provide benefits both for research efforts aimed at unraveling TRAL pathogenesis and for clinical practice with improved identification and monitoring of patients at higher risk of MTZ-induced TRAL. This is of particular importance, since treatment alternatives, especially in secondary progressive MS, are sparse.