Intensified Liposomal Daunorubicin May Offer High Survival Rates without Added Cardiotoxicity for Children with Leukemia


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Treating pediatric leukemia patients with a liposomal formulation of anthracycline-based chemotherapy at an intensified dose during initial treatment may result in high survival rates without causing any added heart toxicity, according to the results of a study published online in Blood.1

Acute myeloid leukemia (AML), is the second most common form of leukemia in children. Standard induction regimens in children typically consist of 3 days of an anthracycline such as daunorubicin or idarubicin and 7 to 10 days of another chemotherapy such as cytarabine. Approximately 60% to 70% of children with AML achieve long-term survival with this combination of drugs.

Anthracycline Toxicity

Recent evidence has suggested that increasing the intensity of induction treatment might improve remission rates and perhaps overall survival in AML patients. However, clinicians have used this approach sparingly in pediatric patients because of documented dose-related anthracycline toxicity in children, particularly the significant risk of damage to the developing heart muscle.

In an effort to increase the effectiveness of this treatment for children with AML but reduce the cardiac risk profile, researchers are now investigating a liposomal formulation of daunorubicin that allows for more targeted delivery of the drug in the cancerous cells and diffuses at a slower pace in the body, which leads to a lower accumulation in the heart. Results from early preclinical studies of the lipid-based formulation suggest that liposomal daunorubicin (DaunoXome) may be effective at higher-than-standard doses without causing added cardiotoxicity.

“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,” said lead study author Ursula Creutzig, MD, PhD, of the Hannover Medical School in Germany. “This unique formulation of daunorubicin might offer us a way to effectively manage AML in these young patients while reducing their risk of experiencing the acute and long-term toxicities associated with traditional regimens.”

Trial Details

Between 2004 and 2010, Dr. ­Creutzig and colleagues randomly assigned 521 patients under age 18 to treatment with either liposomal daunorubicin or idarubicin induction therapy. Patients treated with liposomal daunorubicin received a higher dose (80 mg/m²/d ×3) than the equivalent dose of idarubicin (12 mg/m²/d ×3) during induction. Both groups also received additional treatment with cytarabine and etoposide. High-risk patients (defined roughly as those who were not in the favorable cytogenetic group) also received supplemental treatment with a chemotherapeutic agent (2-CDA) after the induction period. Additional cycles of maintenance treatment were administered to all participants, excluding those who received a stem cell transplant.

Promising Results

After a 5-year observational period, researchers noted similar results in both treatment arms (76% overall survival in the liposomal daunorubicin group vs 75% in the idarubicin group). The probability of event-free survival was also similar in the liposomal daunorubicin (59%) and idarubicin groups (53%), as were the probability of event-free survival results for standard-risk (72% for liposomal daunorubicin vs 68% for idarubin) and high-risk patients (51% vs 46%, respectively).

Overall, treatment with this intensified induction regimen had a similar safety and tolerability profile to the traditional idarubicin dose. Treatment-related mortality was lower in the liposomal daunorubicin group than in the idarubicin group (2/257 vs 10/264 patients), and there were no unusual or persistent toxicities seen when compared with previous related trials.

The team observed generally low rates of cardiotoxicities across the treatment groups in the study, though, fewer events were reported among the liposomal daunorubicin–treated patients than the idarubicin-treated patients. In the liposomal daunorubicin group, there were four reports of severe acute cardiotoxicities, such as functional impairment, vs five events in the idarubicin group. There was a single patient reported to have late cardiotoxicity during follow-up in the liposomal daunorubicin group, as compared with three patients in the idarubicin treatment group.

“These findings signal an important step forward in our goal to identify treatments that can give pediatric patients the best chance for long-term survival with minimal toxic side effects, and we believe the approach could have a number of extended applications. For example, this treatment formulation may be appropriate to use in adults or elderly patients to reduce the toxicity profile, or it may be of value for other malignant diseases in both children and adults,” said Dr. Creutzig. ■

Disclosure: For full disclosures of the study authors, see bloodjournal.hematologylibrary.org.

Reference

1. Creutzig U, Zimmermann M, Bourquin JP, et al: Randomized trial comparing liposomal daunorubicin with idarubicin in induction for pediatric acute myeloid leukemia. Blood. May 23, 2013 (early release online).



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