Measurable residual disease (MRD) status shows value in predicting progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) in the era of targeted therapies, according to an analysis in JAMA Oncology.
In what is believed to be the first meta-analysis of MRD-related CLL trials involving targeted therapies, the findings suggest that MRD as an endpoint in clinical trials, and as a surrogate for PFS, could improve trials and hasten drug development, the researchers said. MRD could figure more prominently in trials and treatment decisions as the CLL field turns toward time-limited therapies, said senior author Talal Hilal, MD, of Mayo Clinic in Phoenix.
CLL disease response categories have not changed much in recent years despite the introduction of new therapies, including BTK inhibitors (BTKis) and BCL2 inhibitors, and advancements in detection of MRD.
Researchers analyzed data from 11 trials, including two single-arm studies with 204 patients and nine randomized studies with 2,561 patients. Seven of the studies reported on first-line treatment. When a trial reported undetectable MRD (uMRD) as less than 0.01%, low MRD as 0.01% to 0.1%, and high MRD as greater than 0.1%, researchers pooled the low and high MRD together as MRD-positive.
When pooled, the uMRD group had an estimated two-year PFS of 91.9% (95% CI 88.8%-95.2%) compared to 75.3% (95% CI 64.7%-87.6%) for the MRD-positive group (p<0.001).
In the first-line setting, the estimated two-year PFS was 93.5% (95% CI 90.9%-96.2%) for the uMRD group and 77.7% (95% CI 64.9%-93.0%) for the MRD-positive group (p<0.001). In the relapsed or refractory setting, the estimated two-year PFS was 83.5% (95% CI 70.8%-98.4%) for uMRD and 68.8% (95% CI 50.2%-94.4%) for the MRD-positive group. This showed there was a difference, but researchers noted this did not meet statistical significance.
Dr. Hilal said MRD has not been seen as a vital tool for assessing the effectiveness of treatments in CLL and long-term disease control — especially in light of BTKis that produce long remissions with continuous treatment but rarely uMRD — but that might soon change.
“As the field moves toward time-limited treatment approaches — for example, venetoclax plus obinutuzumab or venetoclax plus BTKi — we may see a more prominent role for MRD in both clinical trials and clinical practice,” he said.
“New treatments,” Dr. Hilal said, “particularly venetoclax, yield deep responses, so MRD can serve not only as a prognostic marker but potentially as a biomarker for early treatment discontinuation. For example, instead of giving every patient one or two years of targeted therapy, we may be able to stop at six months.”
Dr. Hilal noted that “MRD status trumps traditional CT measurements” but so far has not, in his personal practice, been extending treatments past one year for those on time-limited therapy for someone who remains MRD-positive.
“I do think there might be a role for tailoring treatment in high-risk CLL with potentially longer duration of therapy, but I would like to wait and see what some of the trials that are currently ongoing will show with regard to MRD-guided therapy,” Dr. Hilal said.
Improving clinical research will involve standardizing MRD measurements and timepoints for measuring MRD, he said.
“More evidence showing improved outcomes with MRD-guided treatment approaches will lead to an accumulation of data that may eventually support the role of MRD, not only as a trial endpoint but as a regulatory endpoint that is recognized by the U.S. Food and Drug Administration.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Rios-Olais FA, McGary AK, Tsang M, et al. Measurable residual disease and clinical outcomes in chronic lymphocytic leukemia: a systematic review and meta-analysis. JAMA Oncol. 2024;10(9):1221-1227.
