Seeking higher survival rates and lower side effects in pediatric ALL
Children newly diagnosed with acute lymphoblastic leukemia (ALL) typically receive a 2- to 3-year regimen of chemotherapy drugs. While this treatment results in event-free survival for the majority of young patients, 15 to 20 percent of children relapse and have poor outcomes. In addition, drug toxicities negatively affect their quality of life. A clinical trial, led by Lewis Silverman, MD (DFCI), is testing whether an alternate preparation of asparaginase reduces its side effects, and if a risk-stratified approach to therapy based on minimal residual disease (MRD) leads to better survival rates.
Why this study is important
In this randomized phase III trial, investigators are comparing the efficacy and safety of two different preparations of asparaginase in combination with other chemotherapy drugs. Asparaginase is a universal component of therapy for childhood ALL, but is associated with many side effects including allergic reactions, pancreatitis, and thrombosis. One cohort receives standard E.coli asparaginase by intramuscular injection every week for 30 weeks; another receives PEG-asparaginase intravenously through a central line every 2 weeks. Previous studies have shown that polyethylene glycosylated (PEG) asparaginase – a preparation in which asparaginase is encapsulated within a polyethylene barrier – lasts longer in the body and may be less allergenic than the standard E.coli preparation. Moreover, while E.coli asparaginase can only be given as an intramuscular injection in the US, PEG asparaginase has recently been approved for intravenous administration. “Our hope is to reduce the rate of allergy to asparaginase so that more patients can receive effective doses,” says Silverman. “Children also benefit by not having to get a painful intramuscular injection every week.”
At the same time, a significant objective of this trial is to use MRD as a new biomarker to identify patients at high risk of relapse and to intervene early with more intensive treatments. After one month of chemotherapy, up to 98 percent of children achieve complete remission (i.e., in a bone marrow sample, no leukemia cells can be seen under the microscope). But if chemotherapy is stopped at that point, says Silverman, 100 percent of patients will relapse. “Even though you cannot see leukemia cells, a lot of residual disease is left behind following the initial induction phase” – thus the need for a 2- to 3-year drug regimen.
As more sensitive techniques such as PCR were developed that could measure “invisible” MRD, Silverman and colleagues began correlating MRD levels with outcomes. “We found that about 15 percent of patients with high levels of MRD at the end of the first month of treatment had a very high chance of subsequently relapsing. Now, for the first time, we are acting on that information in this clinical trial.”
At the time of diagnosis, probes are developed from patients’ bone marrow and peripheral blood samples and used at the end of induction to measure MRD; these tests can detect one leukemia cell in 100,000 normal cells, says Silverman. Those patients with high levels of MRD, about 15 percent, are then assigned to a different treatment arm of the study, which includes additional chemotherapeutic agents not typically given to newly diagnosed ALL patients.
The study is also using MRD and other factors to try to reduce long-term side effects of cranial radiation. Although it is effective in preventing relapses in the brain and spinal fluid, cranial radiation is associated with secondary brain tumors and the risk of learning disabilities. Only patients at highest risk of relapse receive this additional treatment.
Protocol title
Pegasparaginase or Asparaginase and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Principal investigator
Lewis Silverman, MD
More information
For eligibility criteria, contact information, and sites, go to NCT00400946 on ClinicalTrials.gov.
—Lonnie Christiansen
