(MRD) that persists following remission induction chemotherapy afor acute lymphocytic leukemia (ALL) is a powerful prognostic factor, new research shows that determining MRD levels in the middle of the remission induction course could be a valuable tool for determining patients at risk for relapse and identifying the best treatment strategies for individual patients.
According to a study of nearly 500 pediatric and adolescent ALL patients published in The Lancet Oncology, patients who had an MRD level ≥1 percent on the 19th day of remission induction therapy had significantly worse 10-year event-free survival compared with patients who had levels <1 percent, regardless of their initial risk classification.
Measuring MRD levels in the middle of remission induction can give clinicians valuable information about how to structure future treatment efforts, first author Ching-Hon Pui, MD, a professor in the department of oncology at St. Jude Children’s Research Hospital in Memphis, Tennessee, told ASH Clinical News. “MRD monitoring is the most powerful way to identify high-risk patients who need more intensive therapy and to help us avoid overtreatment of low-risk patients by reducing their exposure to chemotherapy,” he said.
To reach these conclusions, Dr. Pui and colleagues classified the risk of relapse as low, standard, or high in 498 patients with ALL, according to patients’ baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on MRD levels measured on days 19 and 46 of remission induction therapy. MRD levels were also measured at week 7 of maintenance therapy and at weeks 17, 48, and 120 (the end of treatment).
If the MRD level at day 19 was ≥1 percent, patients were given three additional doses of asparaginase along with their conventional remission induction.
However, despite this intervention and intensive post-remission treatment, groups with higher MRD levels on day 19 still had lower overall 10-year event-free survival rates, as follows:
- Low-risk patients with MRD levels <1 percent: 95.5 percent
- Low-risk patients with MRD levels ≥1 percent: 69.2 percent
- Standard-risk patients with MRD levels <1 percent: 82.9 percent
- Standard-risk patients with MRD levels ≥1 percent: 65.1 percent
Similarly, the investigators found that those low-risk patients who initially had a day 19 MRD level of ≥1 percent but were able to convert to an MRD-negative status by day 46 had a better event-free survival rate after 10 years than those from the same risk group who still had detectable MRD on day 46 (88.9% vs. 59.2%, respectively).
Dr. Pui believes that the results from this study also show that measuring MRD levels just twice during remission induction – rather than multiple times during the more than two years of treatment – was sufficient to guide treatment for most pediatric ALL patients. These findings could also potentially save money and protect patients from risks associated with MRD testing.
The team of investigators from St. Jude Children’s Research Hospital plan to examine the ability of MRD measurements to reduce treatment for patients with an extremely low risk of relapse to improve quality of life and reduce treatment-related morbidity. “By contrast, for patients with MRD levels ≥1 percent on day 19, we will test more intensive or novel therapy during and after remission induction to attempt to improve cure rate,” he added.
Dr. Pui acknowledges, however, that MRD is not a perfect predictor of relapse risk: “For example, relapse occurred in 26 of 430 patients with undetectable MRD at the end of continuation treatment.” By contrast, relapse occurred in only two of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy who were treated with chemotherapy alone. “Research will need to determine if even more sensitive methods of MRD measurement can improve our precision in predicting outcome,” Dr. Pui noted.
Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol. 2015;16:465-74.