Liposomal Daunorubicin: Less Cardiotoxicity in Pediatric AML

Kate Johnson

May 30, 2013

Induction therapy with a liposomal formulation of the anthracycline daunorubicin (DaunoXome, Galen) might allow higher dosing with less toxicity than standard induction therapy in children with acute myeloid leukemia (AML), according to the population-based AML-BFM 2004 study, published online May 23 in Blood.

"We know that the standard induction treatment regimen is effective in pediatric leukemia patients, but recognize that the toxicities associated with this therapy can be damaging to young patients who are still growing and developing," lead study author Ursula Creutzig, MD, from the Hannover Medical School in Germany, said in a statement.

"This unique formulation of daunorubicin might offer us a way to effectively manage AML in these young patients while reducing their risk [for] acute and long-term toxicities associated with traditional regimens," she added.

Liposomal daunorubicin was approved by the US Food and Drug Administration in 1996 as first-line treatment for HIV-associated Kaposi's sarcoma, Dr. Creutzig told Medscape Medical News. Her group recently reported improved outcomes with daunorubicin in relapsed AML (J Clin Oncol. 2013;31:599-607), and she said the approval process for the AML indication has begun in both the United States and Europe.

With standard AML induction therapy, 80% to 90% of children and adolescents can achieve remission. New research suggests that this rate might improve further with more intense dosing, Dr. Creutzig and colleagues report.

"However, dose-related anthracycline toxicity, especially acute and late cardiotoxicity, might limit further treatment intensification in particular in children," they note. The risk for anthracycline cardiotoxicity is higher in children than in adults.

The active substances in the "liposomally entrapped" formulation of daunorubicin (L-DNR) are chemically identical, but the pharmacokinetics of L-DNR are more favorable, leading to lower accumulation in the heart and minimal cardiotoxicity in animal models.

The AML-BFM 2004 study was conducted from March 2004 to April 2010 in Austria, the Czech Republic, Germany, and Switzerland. Dr. Creutzig and colleagues randomized 521 patients younger than 18 years to either L-DNR induction (n = 257) or standard induction with idarubicin (n = 264).

In general, standard induction therapy in children and adults with AML consists of 3 days of anthracycline (daunorubicin ≥60 mg/m², idarubicin 10 to 12 mg/m², or the anthracenedione mitoxantrone 10 to 12 mg/m²) and 7 to 10 days of cytarabine (100 to 200 mg/m² per day), the authors explain.

For this study, the L-DNR dose (80 mg/m² per day for 3 days) was higher than the equivalent dose of idarubicin in the control group (which corresponded to 60 mg/m² per day for 3 days of L-DNR).

Both groups also received cytarabine and etoposide.

At 5 years, overall survival was similar in the L-DNR and idarubicin groups (76% vs 75%; P = .65), as was event-free survival (59% vs 53%; P = .25).

The safety and tolerability profiles were also similar in the 2 groups, although there was less treatment-related mortality in the L-DNR group than in the idarubicin group (0.8% vs 3.8%; P = .04).

Because response rates and long-term outcomes were similar in the 2 groups, the authors conclude that the "mild dose increase did not translate into largely different efficacy."

They add that "most acute toxicities, including hematologic and infectious complications, were in the expected range or tended to be lower" with L-DNR than with idarubicin.

"Cardiotoxicity was low after induction in both arms, and during follow-up, only 1 patient in the L-DNR arm and 2 patients in the idarubicin arm required treatment with ACE inhibitors. However, the assessment of long-term anthracycline cardiotoxicity requires longer follow-up," they note.

Coauthor Dirk Reinhardt, MD, from the Hannover Medical School, is member of the advisory board of Galen. The other authors have disclosed no relevant financial relationships.

Blood. Published online May 23, 2013. Abstract

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