Liposomal Chemo Combination No Better Than Standard Induction in Pediatric AML

Liposomal daunorubicin and cytarabine (Vyxeos) didn’t hold up to standard daunorubicin/cytarabine induction therapy in children and young adults with newly diagnosed acute myeloid leukemia (AML), a phase III trial from the Children’s Oncology Group showed.

Among patients with FLT3 wild-type AML, the 2-year event-free survival (EFS) rate from study entry was 62.2% with standard induction versus 51.2% with liposomal daunorubicin and cytarabine (P=0.011), reported Todd Cooper, DO, of Seattle Children’s Hospital, and colleagues in the Journal of Clinical Oncology.

While disease-free survival for patients with high-risk AML was comparable between arms, it was significantly lower among patients with low-risk disease assigned to liposomal treatment, with a 2-year EFS rate from the end of the first induction cycle of 57.5% versus 73.8% with standard induction (P=0.001).

Moreover, the 2-year cumulative incidence of relapse from the end of the first induction cycle for patients who continued therapy was higher in the liposomal group (44.3% vs 31.7%, P=0.005).

These results demonstrated that “this specific formulation of daunorubicin and cytarabine is not the right choice for pediatric patients with [newly diagnosed] FLT3 wild-type pediatric AML,” wrote Christian M. Zwaan, MD, PhD, and Alwin Huitema, PhD, of the Princess Máxima Center for Pediatric Oncology in Utrecht, the Netherlands, in an accompanying editorial.

Cooper and colleagues noted that while the intensification of chemotherapy has helped improve outcomes in pediatric AML, EFS and overall survival (OS) rates have plateaued.

Anthracyclines are essential for cure, but are associated with significant acute and late toxicities, including early cardiotoxicity associated with significantly decreased EFS and OS, and substantial late cardiac morbidity/mortality in pediatric AML survivors, they explained.

“Thus, alternative therapeutic strategies that mitigate cardiotoxicity while improving survival are essential,” they wrote.

The daunorubicin/cytarabine combination was approved by the FDA for adults with newly diagnosed treatment-related AML or AML with myelodysplasia-related changes in 2017, with that approval later extended to children ages 1 year and older.

Cooper and team hypothesized that liposomal daunorubicin and cytarabine given during induction cycles 1 and 2 would improve outcomes compared with standard daunorubicin/cytarabine induction.

They suggested that the unexpected results from the trial may have been influenced by a number of factors, including a difference in dosing from the FDA-approved adult dose, high rates of withdrawal from protocol therapy, and the exclusion of patients with diagnoses for which liposomal daunorubicin and cytarabine is approved.

Zwaan and Huitema pointed out that there are two pediatric AML frontline trials in Europe that are investigating this therapy, including the ongoing AIEOP-BFM-AML 2020 study. That trial is randomly assigning children with newly diagnosed AML to two cycles of liposomal daunorubicin and cytarabine compared with idarubicin, etoposide, and cytarabine in the first induction cycle, and cytarabine and mitoxantrone in the second.

Whether that trial will confirm these study results is “crucial to provide a final assessment” on the activity of liposomal daunorubicin and cytarabine in pediatric patients with newly diagnosed AML, Zwaan and Huitema wrote. “However, unless the AIEOP-BFM study sheds a different efficacy light” on these findings, liposomal daunorubicin and cytarabine should not supplant regular induction chemotherapy in this population, “even if cardiac toxicity can be reduced.”

This study was an open-label, multicenter, randomized trial that included patients ages 21 years and younger with newly diagnosed AML. Cooper and team enrolled 886 patients before randomization assignment was stopped because of futility; 721 evaluable patients were randomly assigned to two cycles of standard daunorubicin/cytarabine induction therapy or liposomal daunorubicin and cytarabine. All patients also received gemtuzumab ozogamicin (Mylotarg) during the first induction cycle.

Post-induction chemotherapy was given according to risk assignment made at the end of induction cycle 1. Those with high-risk AML received consolidation with allogeneic hematopoietic stem cell transplantation, while low-risk patients received chemotherapy alone.

During the first induction cycle, the occurrences of grade ≥3 oral mucositis, alanine aminotransferase increases, rash, and hypertension were significantly higher with liposomal daunorubicin and cytarabine. During induction cycle 2, febrile neutropenia, rash, and hypertension were higher.

Cooper and colleagues noted that patients treated with standard daunorubicin and cytarabine induction therapy received dexrazoxane as a cardioprotectant during anthracycline-containing cycles. They reported that there were no significant differences in site-reported cardiac adverse events when comparing study arms during induction and intensification cycles.