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A Win for Less-Intense Therapy in Pediatric ALL

Intermittent treatment with a widely used drug for pediatric acute lymphoblastic leukemia (ALL) achieved disease control similar to continuous therapy while significantly reducing toxicity, a randomized trial showed.

The 5-year disease-free survival (DFS) rate was 92.2% with intermittent pegylated asparaginase (PEG-asp) and 90.8% with continuous therapy. The 3-year cumulative incidence of any asparaginase-related toxicity was 50% lower in the patients who received intermittent therapy, a difference confirmed in sex- and age-adjusted analyses.

Key toxicities were numerically lower in the intermittent arm, Birgitte Klug Albertsen, MD, PhD, of Aarhus University Hospital in Denmark, and coauthors reported in the Journal of Clinical Oncology, including pancreatitis and thromboembolism.

“The current study demonstrates that after the first five doses of PEG-asp, additional PEG-asp at just 6-week intervals reduces toxicity and costs with equal efficacy compared with treatment every 2 weeks,” the authors concluded.

Since the 1960s, cure rates for pediatric ALL have improved dramatically to more than 90% today, and event-free survival approaches that rate, the author of an accompanying editorial noted. However, the progress has occurred at a significant cost of morbidity and mortality with various post-induction intensification strategies.

“Thus, contemporary ALL studies must ask two questions when treatment intensification is considered and ideally should perform a risk-benefit analysis,” wrote Stephen P. Hunger, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania. “Will more therapy improve survival, and what are the short- and long-term adverse effects of more therapy?”

He declared the study results “definitive” and said they have “important implications for contemporary ALL therapy and are also relevant to other cancers with high cure rates and survival expected for decades.”

“We know that a substantial majority of children with ALL can be cured with contemporary therapy and that many of them could be cured with less therapy, presumably leading to fewer short- and long-term adverse events,” Hunger continued. “It is, of course, critical to focus attention on high-risk subsets of patients who need more effective therapy. However, it is quite likely that we have reached the limits of conventional chemotherapy, and more cytotoxic therapy is not the answer.”

Albertsen and colleagues reported findings from the multicenter randomized Nordic Society for Pediatric Hematology Oncology (NOPHO) ALL2008 trial that compared two strategies of post-induction therapy with PEG-asp for children with ALL. Enrollment occurred from July 1, 2008 to March 1, 2016 and was limited to patients with Philadelphia chromosome-negative B-cell precursor or T-cell ALL. Patients were from ages 1 to 17.9 years, had non-high-risk disease, and had received treatment in accordance with NOPHO recommendations.

All patients received five doses of PEG-asp every 2 weeks, and then were randomized to receive three additional doses at 6-week intervals (intermittent) or 10 doses at 2-week intervals (standard). The primary endpoint was noninferiority of DFS for the comparison of the intermittent versus the standard treatment schedule with a noninferiority limit of 6%. Toxicity was a secondary endpoint, and investigators prospectively documented the occurrence of PEG-asp-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism.

Data analysis included 625 patients who had median follow-up of 4.1 years. The trial ended early after an interim analysis showed virtually identical DFS and a substantial reduction in toxicity for patients randomized to the intermittent arm.

For the secondary endpoint of cumulative toxicity, the 3-year rates were 9.3% in the experimental arm and 18.1% in the standard arm (P=0.002). Overall, children 10 or older had significantly more toxicity than did younger patients (32.8% vs 9.8%, P<0.001), but toxicity did not differ between boys and girls (13.0% vs 14.5%) or between intermediate- and standard-risk patients (15.3% vs 12.7%).

Analysis of the four major PEG-asp-associated toxicities showed a significant difference in pancreatitis (1.3% vs 5.8%, P=0.002) favoring intermittent therapy and numerically lower rates for hypersensitivity, osteonecrosis, and thromboembolism.

The study was supported by the Danish Childhood Cancer Foundation.

Albertsen disclosed relationships with Shire and Erytech Pharma. Coauthor Mats Heyman disclosed relationships with Pfizer and Shire.

Hunger disclosed relationships with Amgen, Merck, Pfizer, Erytech, Jazz Pharmaceuticals, and Novartis.