Author(s): Annegret Reichwagen aff1 , Marita Ziepert aff2 , Markus Kreuz aff2 , Ute Gödtel-Armbrust aff1 , Tanja Rixecker aff3 , Viola Poeschel aff3 , Mohammad Reza Toliat aff4 , Peter Nürnberg aff4 , Mladen Tzvetkov aff5 , Shiwei Deng aff1 , Lorenz Trümper aff6 , Gerd Hasenfuss aff7 , Michael Pfreundschuh aff3 , Leszek Wojnowski [*] aff1
anthracyclines; cardiotoxicity; clinical trial; heart failure; RICOVER-60; SNP
Anthracyclines have been applied for half a century against various hematopoietic and solid tumors. A major limitation to their use is anthracycline-induced cardiotoxicity (ACT), acutely manifesting as arrhythmias, pericarditis-myocarditis or acute left ventricular failure, and chronically as congestive heart failure [1 ]. Oxidative stress due to anthracycline 'redox cycling' is currently the most widely accepted hypothesis of chronic ACT, although the condition cannot be prevented with antioxidants [2 ]. This suggests a more complex pathophysiology, which may involve poisoning of topoisomerase II beta in cardiomyocytes [3 ]. Fittingly, the EDTA-like hydrolysis product of dexrazoxane, the only clinically proven prophylactic drug against chronic ACT [2 ], prevents oxidative stress via iron chelation. Additionally, the parent compound degrades the putative cardiac anthracycline target topoisomerase II beta [3 ].
Why only some and exactly which patients will develop ACT has been the subject of intense investigations, as predisposed patients could be subjected to preventive measures such as dexrazoxane or treated with anthracycline-free regimens as the latter ones become available. Conversely, anthracycline dose escalation could improve treatment outcomes in patients more resistant to ACT. In addition to high cumulative anthracycline doses, especially when combined with mediastinal irradiation or cardiovascular co-morbidities, ACT is more common in females, children and the elderly [4 ]. There is also emerging evidence for a genetic component in ACT, which has been addressed in a dozen of studies over the past decade. Variants found associated with ACT in at least two different study cohorts represent a total of 11 genes (Table 1), all but one (HNMT ) of which have been linked either to anthracycline pharmacokinetics or to oxidative stress.
In adults, ACT has been repeatedly associated with gene variants of the subunits of the NADPH oxidase enzyme complex [12,13,15 ], and of the anthracycline transporter ABCC2 [12,14 ]. The involvement of the NADPH oxidase in ACT [12,13 ] is consistent with the cardiac resistance to doxorubicin observed by two different laboratories in mice deficient for a subunit of this enzyme [ 12,16,17 ]. Supporting biochemical evidence also exists for ABCC2 [18 ].
Whereas these associations open a long-term perspective of ACT reduction in adults via genetic stratification-based treatment adjustment, they are not yet ready for prospective clinical validation and need to be reproduced in further cohorts. In the following we describe the results of a genetic ACT study conducted on patients enrolled in the RICOVER-60 study [19 ]. The study, registered at www.clinicaltrials.gov as NCT00052936, comprised 61-80-year-old patients with aggressive CD20+ B-cell lymphomas treated with six or eight cycles of CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisolone, administered at intervals of 2 weeks) with or without rituximab. Importantly, both the study cohort and the treatment were relatively...