Lower Intensity Chemotherapy Fails in Pediatric ALL Trial

SAN DIEGO-Among pediatric acute lymphoblastic leukemia (ALL) patients who have favorable prognosis, an attempt to reduce the burden of chemotherapy by using lower intensity delayed intensification failed to show better outcomes, according to a new study presented (abstract 4) at the American Society of Hematology (ASH) 58^th Annual Meeting and Exposition, held December 3–6.

In fact, the shortened chemotherapy arm led to an increased number of relapsed patients, said lead author Martin Schrappe, MD, of the University Medical Center Schleswig-Holstein, Kiel, Germany.

Schrappe and colleagues enrolled 1,164 patients, the majority of them under age 10, from Germany, Italy, Austria, and Switzerland into a randomized trial to compare a protocol for delayed re-intensification with a standard protocol in order to reduce treatment burden in the group of patients with best treatment response and lowest risk of relapse. The duration of the protocol was shortened from 49 to 29 days and the dose of dexamethasone was reduced by 30% and the doses of vincristine, doxorubicin, and cyclophosphamide were reduced by 50%.

Only patients who were defined as minimal residual disease (MRD) standard risk negative were included in the trial.

With a median follow-up of 8.6 years, the 4-year disease-free survival (DFS) was 91.8% for the 584 patients in the shortened chemotherapy arm and 95.8% for the 579 patients in the extended chemotherapy arm. The 4-year cumulative incidence of relapse (CIR) was 6.3% in the shortened chemotherapy arm and 3.2% in the extended chemotherapy arm.

At 8 years, DFS was 89.2% and 92.3%, CIR was 8.7% and 6.4%, and overall survival was 96.1% and 98%, respectively, for the shortened vs extended chemotherapy arms. Also, at 8 years, the cumulative incidence of secondary malignancies was twice as high (1.3%) with shortened chemotherapy compared with extended chemotherapy (0.6%), which was “unexpected” and has no genetic reason, Schrappe said.

The incidence of death in remission was comparable between the two groups, and the rate of grade III/IV infections used as an indicator for relevant toxicity was essentially the same, he said.

In conclusion, Schrappe said “in childhood ALL patients with most favorable prognosis, as predicted by complete MRD response already by day 33, an attempt to reduce the burden of chemotherapy by lower intensity delayed intensification was not successful. We observed 50% more relapses in less intensively treated patients. Only the randomized approach in a large cohort of ALL patients could detect this significant and clinically relevant difference. Any treatment modification in patients with excellent prognosis should be carried out with large caution under controlled conditions.”

Stephen B. Hunger, MD, of the Children’s Hospital of Pennsylvania, who introduced Schrappe’s plenary presentation, stated: “there are patients who can be cured with less therapy, including perhaps a much more dramatic reduction in therapy than was attempted here. However, we need a different strategy to identify those patients.”

He said that strategy might incorporate clinical risk factors, such as age and initial white blood cell count, tumor genetics, and even more sensitive measures of MRD.

“This study is important and shows us that randomized trials are critically important when we try to reduce treatment for a highly curable cancer,” said Hunger.