Study Finds No Benefit With Post-Induction Treatment Intensification in Children With ALL

According to results from the Children’s Oncology Group AALL0331 trial, pediatric patients with standard-risk B-cell acute lymphocytic leukemia (ALL) had a high rate of overall survival (OS) at 6 years, even without intense consolidation treatment and intensifying consolidation treatment. These findings, which were published in the Journal of Clinical Oncology, suggest that “many children can be spared the toxicities associated with [intensified consolidation] without compromising a survival benefit.”

In a previous analysis from AALL0331, intensified post-induction therapy improved survival outcomes in children with high-risk B-cell ALL, prompting researchers to investigate whether those with standard-risk disease would benefit similarly, explained Kelly W. Maloney, MD, from the University of Colorado, and co-authors.

Per study protocol, all 5,377 patients (range = 1-9 years) enrolled in the trial received a three-drug induction regimen of dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as standard risk-low (SR-low; n=1,857), standard risk-average (SR-
average; n=1,500), or standard risk-high (SR-high; n=635). Participants then received risk-adjusted post-induction therapy.

In the SR-low group, patients were randomized to receive regimens with or without four additional doses of PEG.

In the SR-average group, patients were randomized to receive either:

  • standard 4-week consolidation (n=745)
  • 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (n=755)

In the SR-high group, patients were assigned to receive full augmented BFM therapy, which included two interim maintenance and delayed-intensification phases.

During induction, 25 patients (0.47%) in the entire AALL0331 population died; of the remaining patients, 5,171 (98%) had bone marrow blasts measured at day 29 and were included in the survival analysis. For all evaluable patients, outcomes were “outstanding,” the researchers wrote. The 6-year event-free survival (EFS) and OS rates were 88.96% and 95.54%, respectively.

Outcomes were similarly high in the group of 1,500 patients with SR-average disease, the authors reported, regardless of the type of post-induction therapy.

For example, the 6-year rate of continuous complete remission (CCR) was 87.8% in the standard consolidation group, compared with 89.1% in the intensified consolidation group (p=0.52 for comparison). The 6-year OS rates also were high and similar to those achieved in the overall study population (95.78% for standard consolidation vs. 95.15% for intensified consolidation; p=1.0).

The investigators then looked at response and survival outcomes according to measurable residual disease (MRD) status at the end of induction therapy. As expected, those with SR-average disease and MRD of 0.01% to <0.1% had an inferior outcome compared with those with lower MRD levels, with 6-year CCR and OS rates of 77.25% and 91.42%, respectively. However, there was still no benefit with intensified consolidation over standard consolidation (6-year CCR rate = 77.07% vs. 77.46%; p=0.71).

Patients who received standard consolidation also appeared to be able to avoid some of the additional toxicities seen with the intensified regimen, which was associated with significantly more hematologic and infectious toxicities. For example, grade 3/4 neutropenia occurred in 12.7% of patients in the standard consolidation group, versus 62% of the intensified consolidation group (p<0.001), and infections occurred in 4.7% vs. 23% (p<0.001). However, the authors noted that the incidence of non-relapse mortality was similar (2 deaths in the standard group and 1 death in the intensified group).

The researchers also highlighted that patients with SR-high disease who received full BFM therapy had high rates of CCR and OS (85.55% and 92.97%, respectively).

“Although intensifications that improve outcomes for those with [high-risk disease] often improve EFS and OS for those [with standard-risk disease], the morbidity of intensified treatment must be balanced with the overall high cure rate in patients with standard-risk disease,” Dr. Maloney and co-authors wrote. “Taken together, these results suggest that further intensifying conventional therapy will not improve cure rates and that novel approaches are needed,” the authors concluded.

The implications of this study are potentially limited by the number of treatment protocol amendments required throughout the trial, including adjustments to methotrexate and dexamethasone dosing schedules.

The authors report no relevant conflicts of interest.

Reference

Maloney KW, Devidas M, Wang C, et al. Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: results of Children’s Oncology Group trial AALL0331. J Clin Oncol. 2019 December 11. [Epub ahead of print]