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 asso-
ciated with [intensified consolidation] without compromising a
survival benefit.”
In a previous analysis from AALL0331, intensified post-
induction therapy improved survival outcomes in chil-
dren 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 in-
duction 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 inter-
im 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 consol-
idation 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 consolida-
tion 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 ap-
peared to be able to avoid some of the additional toxicities
seen with the intensified regimen, which was associated
with significantly more hematologic and infectious toxici-
ties. 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 re-
sults suggest that further intensifying conventional ther-
apy will not improve cure rates and that novel approaches
are needed,” the authors concluded.
The implications of this study are potentially limit-
ed 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]
March 2020
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