Recognizing the potential for copper-related toxicities from liposomal daunorubicin--cytarabine

RE: Recurrent and reversible bilateral palmar blue discoloration following administration of liposomal daunorubicin-cytarabine (VyxeosR ) for acute myeloid leukemia with myelodysplasia-related changes (Published online 13 December 2020): The authors describe a patient with blue discoloration of the palms after treatment with liposomal daunorubicin-cytarabine. The presentation is unlike the more common palmar-plantar erythrodysesthesia (hand-foot syndrome) seen with conventional chemotherapeutic agents including anthracyclines and cytarabine. It should be noted that cytarabine is often associated with dermatologic adverse events including erythematous and morbilliform rash. Anthracyclines and mitoxantrone are associated with discoloration of the urine, nails, and sclera. Copper gluconate is an excipient of liposomal daunorubicin-cytarabine which is necessary for liposomal retention of both daunorubicin and cytarabine. The product is a characteristic deep purple color as a result of the copper content. Reconstituted liposomal daunorubicin-cytarabine solution contains 5mg/mL of copper gluconate, and a treatment course consisting of induction, re-induction, and two cycles of consolidation delivers 764mg/m of copper gluconate, or 106mg/m of elemental copper. As a reference point, the Tolerable Upper Intake Level of copper is 10mg/day. Other cases of skin discoloration from copper exposure (both topical and systemic) have been reported. Exposure to copper in large quantities may cause intravascular hemolysis (if given by the intravascular route), neurologic symptoms, rhabdomyolysis, cardiac and renal failure, and other severe toxicities. Thankfully, it appears the patient had no permanent sequelae, and the skin discoloration resolved. Acute copper toxicity including liver failure is of concern in patients with Wilson’s disease. Current package labeling warns against the use of liposomal daunorubicin-cytarabine in patients with Wilson’s disease unless the benefits outweigh the risks, and with consultation with experts. This further highlights the high copper content of the product. The patient presented by Triesel and colleagues had a history of hereditary hemochromatosis, a disorder of iron overload. Although this is of unclear significance to the case, it is potentially of interest, as copper and iron share metabolic pathways and copper may accumulate in hemosiderin of patients with iron overload disorders. While copper-related toxicities from the drug do not appear to be common, increased systemic copper concentrations should be considered as a cause of blue skin discoloration in this and other patients receiving liposomal daunorubicin-cytarabine. It is important to consider excipients of medications as potential culprits of adverse drug reactions. This includes excipients present in novel medication formulations, which may or may not be consistent with those of the original compounds. As the use of liposomal daunorubicincytarabine expands, clinicians should recognize the potential for copper-related toxicities.