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Hematologic Malignancies A Review of Liposomal Daunorubicin in the Treatment of Acute Leukemia Kim Klein, MD 1 and Gertjan L Kaspers, MD, PhD 2 1. Medical Doctor; 2. Professor and Head of Department of Pediatric Oncology, VU Medical Centre, Amsterdam, The Netherlands Abstract Liposomal forms of anthracyclines, such as liposomal daunorubicin (L-DNR), have been developed in order to reduce the dose-limiting toxicity, especially cardiotoxicity. Efficacy and reduced toxicity of L-DNR have been demonstrated in several in vitro and small phase I/II clinical studies. This has led to three recent randomized controlled trials in which efficacy and toxicity of L-DNR in acute myeloid leukemia (AML) patients was evaluated. In elderly, poor-risk AML patients, free DNR was compared with higher doses of L-DNR. This study demonstrated similar complete remission (CR) rates without increasing cardiotoxicity. Overall survival (OS) was slightly better in the L-DNR-arm, but when accounting for risk profiles the OS in the L-DNR arm was significantly better. In pediatric AML, induction therapy with L-DNR was compared with induction with idarubicin. Results showed similar event-free survival (EFS) and OS rates, but less cardiotoxicity with L-DNR. Subgroup analysis demonstrated better results of EFS and OS in core-binding factor AML with L-DNR. Reinduction therapy (fludarabine, cytarabine, granulocyte-colony stimulating factor ± L-DNR) in pediatric relapsed/refractory AML demonstrated higher CR rates in the L-DNR-arm. EFS and OS rates did not significantly improve in the L-DNR arm, but subgroup-analysis showed better results of EFS and OS in core-binding factor AML. The role of L-DNR also seems promising in patients with poor risk, relapsed/refractory ALL, apparently leading to higher CR rates and OS compared with standard regimes. But it should be noted that reports are scarce and no randomized controlled trials have been performed. This article demonstrates that L-DNR improves early treatment response in relapsed AML patients, or equal early treatment response in newly diagnosed AML compared with other anthracyclines, with similar or reduced toxicity. Higher dosages of L-DNR can be administered, without increasing (cardio)toxicity. Nevertheless, prognosis in refractory/ relapsed leukemia remains poor and identifying new therapeutic targets remains necessary—as well as optimization of treatment schedules with conventional agents, including L-DNR. Keywords Liposomal daunorubicin, DaunoXome ® , liposomal anthracyclines, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia Disclosure: Kim Klein, MD, has no conflicts of interest to declare. Gertjan L Kaspers, MD, PhD, is a consultant for Galen Ltd. Acknowledgements: We thank national and international colleagues for interesting discussions on the use of liposomal anthracyclines including liposomal daunorubicin in acute leukemias. Received: August 16, 2013 Accepted: September 1, 2013 Citation: Oncology & Hematology Review (US), 2013;9(2):142–8 Correspondence: Gertjan L Kaspers, MD, PhD, Pediatric Oncology/Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E: [email protected] Use of Anthracyclines in Acute Leukemia Anthracyclines have been part of oncology treatment protocols since the 1980s, and antileukemic effects have been proved decades ago. Although anthracyclines are the keystone of leukemia treatment, there is no consensus for the optimal formulation, dose, or schedule in treating acute leukemia. 1 Various anthracyclines have been evaluated in randomized clinical trials for their efficacy and toxicity. Due to the good antileukemic effect, most protocols contain a relatively high dose of anthracyclines. Unfortunately, anthracyclines have many side effects, of which cardiotoxicity (especially reduced ejection fraction and heart failure) is one of the most important. Cardiac muscle cells have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents such as anthracyclines. Toxicity ranges from treatable arrhythmias to potentially lethal conditions such as myocardial ischemia and cardiomyopathy. Endomyocardial biopsies in anthracycline-induced cardiomyopathy demonstrate sarcoplasmic reticulum dilation, vacuole formation, myofibrillar dropout, and necrosis. 2,3 142 Cardiotoxicity can be a problem during treatment, but is especially known to occur in survivors of (childhood) cancer, as late effect. 4–6 Acute cardiotoxicity is in fact a risk factor for the development of late cardiotoxicity, and one of the risk factors for acute toxicity is administration of anthracyclines by intravenous push, leading to high peak levels which are apparently cardiotoxic. 7,8 Therefore, pediatricians always recommend intravenous infusion of anthracyclines for at least 1 hour. 4 Cumulative dosages of anthracyclines above 300 mg/m² (depending on which review is employed) and high peak doses have been associated with clinically significant cardiotoxicity and are therefore widely debated, especially in pediatric oncology. 3,4,7–10 Indeed, because of the development of the heart muscle, children are more vulnerable to drug-induced cardiotoxicity than adults. 11 However, elderly patients can also be vulnerable because of pre-existing cardiac disease, and clinically relevant late cardiotoxicity has been reported in middle-aged adults treated with relatively high cumulative doses of anthracyclines as well. 8 © Tou c h M E d ica l ME d ia 2013