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MRD may guide augmented post-remission treatment in pediatric ALL
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Children and adolescents with acute lymphoblastic leukemia who had minimal residual disease at the end of remission induction therapy demonstrated improved outcomes with augmented post-remission therapy compared with standard treatment, according to study results.
However, patients who received augmented therapy experienced higher rates of adverse events, results showed.
Ajay Vora, MD, of the department of pediatric hematology at Sheffield Children’s Hospital in the United Kingdom, and colleagues evaluated data from 533 patients with ALL. Patients ranged in age from 1 to 24 years. All patients had minimal residual disease (MRD) of ≥0.01% after 29 days of induction therapy.
Vora and colleagues assigned 266 patients to standard post-remission therapy and 267 patients to augmented post-remission therapy. Those in the augmented cohort received eight additional doses of pegylatedasparaginase, 18 doses of vincristine and escalated-dose IV methotrexate without folinic acid rescue during interim maintenance courses.
Median follow-up was 70 months (interquartile range, 52-91).
Five-year rates for DFS were significantly higher in the augmented therapy cohort (89.6% vs. 82.8%; OR=0.61; 95% CI, 0.39-0.98).
More patients who received augmented therapy achieved 5-year OS (92.9% vs. 88.9%; OR=0.67; 95% CI, 0.38-1.17); however, this difference was not statistically significant.
Patients assigned augmented therapy experienced higher rates of asparaginase-related hypersensitivity (6.7% vs. 0.8%), asparaginase -related pancreatitis (3% vs. 0.4%), IV methotrexate-related mucositis (4.1% vs. 1.1%) and methotrexate-related stomatitis (18% vs. 4.5%).
Michael E. Rytting
“To reduce the toxicity of augmented therapy, and based on the results of a US Childhood Cancer Group study of NCI high-risk patients that showed no benefit from a second delayed intensification course, MRD high-risk patients receive only one delayed intensification course in our ongoing trial, UKALL 2011,” Vora and colleagues wrote. “In the future, new drugs designed to target leukemia-specific receptors and proteins could replace elements of conventional chemotherapy regimens responsible for some of the major toxicities, thereby reducing toxicity while retaining the overall efficacy of treatment, as has already been demonstrated for Philadelphia chromosome-positive ALL.”
The clinical rationale to test for MRD still needs to be substantiated by data from ongoing trials, Michael E. Rytting, MD, of the departments of pediatrics and leukemia at The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.
“MRD might successfully guide therapy decrements in selected patients. Until now, however, little to no evidence had been published from randomized trials showing that intensified chemotherapy can overcome the poor prognosis of MRD positivity,” Rytting wrote. “Results are pending from large, ongoing trials (eg, NCT01406756) that are intensifying therapy by adding agents such as clofarabine [Clolar, Genzyme] or by using early transplant for MRD-positive patients. Hopefully, information from these trials will further support the use of MRD status in treatment decision-making to improve cure rates in children and young adults with precursor B-cell ALL who have a less-than-optimal response to treatment.”
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Disclosure: The researchers report no relevant financial disclosures. Rytting reports no relevant financial disclosures.
Perspective
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Daniel S. Wechsler, MD, PhD
The level of minimal residual disease (MRD) in pediatric patients with ALL is a sensitive and specific predictor of relapse. Patients with undetectable or low MRD at the end of induction therapy have a very low risk of relapse, and the intensity of their post-remission anti-leukemia therapy may be reduced without sacrificing excellent EFS rates. Persistent MRD (>0.01%) at the end of induction is associated with worse outcomes, and it has been presumed that augmenting post-remission therapy could lead to improved EFS. Vora et al now show for the first time that this is, in fact, the case.
In a large UK ALL study spanning almost 8 years and involving more than 3,000 patients, Vora et al randomly assigned 533 patients with end-induction MRD levels of >0.01% to receive standard or augmented (more PEG-asparaginase, vincristine and methotrexate) therapy. Patients treated with augmented therapy had a 5-year EFS that was significantly better than those who received standard therapy (89.6% vs. 82.8%, P=.04), although 5-year OS was not statistically significantly different. Not surprisingly, patients who received augmented therapy had more adverse events (asparaginase-associated hypersensitivity and pancreatitis, and methotrexate–related mucositis and stomatitis). Importantly, this excess toxicity was not associated with increased treatment-related mortality.
The results of this study confirm the presumption that intensifying therapy for MRD-positive pediatric ALL patients can result in improved EFS, mirroring the observation that MRD-negative patients can tolerate reduced-intensity therapy. These findings bring us ever closer to the idea of precision oncology, in which the intensity of therapy can be tailored to individual patient response.
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