MRD levels can identify appropriate therapy for children with ALL

Pediatric patients with acute lymphoblastic leukemia and undetectable minimal residual disease levels can safely receive lower-dose chemotherapy without jeopardizing their survival, according to study results from the Dutch Childhood Oncology Group.

“In the last 5 decades, survival rates for children with ALL have improved by intensifying chemotherapy for all patients,” Rob Pieters, MD, chief medical officer of Princess Maxima Center for Pediatric Oncology in Bilthoven, Netherlands, and colleagues wrote. “Assessment of early therapy response by measuring MRD is the strongest predictor of survival.”

Patients are categorized by MRD levels as standard risk, intermediate risk or high risk after initial therapy. Pieters and colleagues sought to determine whether risk stratification could serve as a means to reduce or intensify therapy without threatening outcomes in these patient populations.

The study included data from 778 patients, 686 of whom were stratified as standard risk (n = 198), intermediate risk (n = 460) or high risk (n = 28) after first- or second-line chemotherapy.

Patients in the standard-risk group received a substantial chemotherapy reduction, whereas patients in the intermediate- and high-risk groups had their chemotherapy regimens intensified.

The researchers compared outcomes to those of historical controls.

Median follow-up was 80 months (range, 36-125).

Thirteen patients died during induction, due to infection (n = 8), intracerebral bleeding or infarction (n = 2), multiorgan failure (n = 1), or unknown causes (n = 2).

Two patients did not achieve complete remission; the remaining 763 patients (98%) achieved complete remission.

Twenty patients died while in complete remission, largely due to infection (n = 13). Other causes of death included stem cell transplant–related causes (n = 4), sudden death (n = 2) and pancreatitis (n = 1).

The entire cohort had a 5-year EFS rate of 87% (standard error [SE], 1.2%) and OS rate of 91.9% (SE, 1%). Relapse occurred in 69 patients (8.9%), with a 5-year cumulative incidence of relapse of 8.3% (SE, 1%). The rate of isolated central nervous system relapse was 1.4% (SE, 0.4%).

The standard-risk group had a 5-year EFS rate of 93.1% (SE, 1.9%) and OS rate of 99% (SE, 0.7%). The cumulative incidence of relapse was 6.4% (SE, 1.8%). Relapse occurred in 15 patients and four patients died due to relapse (n = 2), chickenpox (n = 1) or second malignancy (n = 1).

The 5-year EFS rate among standard-risk patients was not significantly lower than that of historical controls (98%; SE, 2%). Chemotherapy reduction was deemed safe for this group.

Intermediate-risk patients treated with intensified therapy had a 5-year EFS rate of 88.9% (SE, 1.5%), significantly higher than that of historical controls (76%; SE, 6%; P = .056). This cohort had an OS rate of 93.2% (SE, 1.2%) and a cumulative incidence of relapse of 8.4% (SE, 1.3%).

High-risk patients treated with intensified therapy had a significantly higher EFS rate (75.3%; SE, 4.8%) than historical controls (16%; SE, 8%; P < .001). The cohort had an OS rate of 81.5% (SE, 4.3%) and a cumulative incidence of relapse of 12.3% (SE, 3.7%).

The researchers acknowledged a limitation in the study’s comparison with historical cohorts, which may have had differing proportion and composition of risk groups.

“Nevertheless, we conclude that chemotherapy can be substantially reduced without jeopardizing survival in one-quarter of children with ALL who have undetectable MRD levels after induction,” Pieters and colleagues wrote. “Outcomes of patients with intermediate and high MRD levels were improved by more intensive therapy. Overall, outcomes improved significantly compared with those of patients on earlier Dutch Childhood Oncology Group protocols.” – by Cameron Kelsall

Disclosure: Pieters reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.