Interim MRD May Help Direct Individual Treatment for CLL

Interim minimal residual disease (MRD) status may serve as a useful risk stratification measure in patients with chronic lymphocytic leukemia (CLL) being treated with standard fludarabine, cyclophosphamide, and rituximab (FCR), according to the results of a prospective study published in Leukemia.

Based on the results of this study, and using interim MRD, researchers led by Philip A. Thompson, MD, of the University of Texas MD Anderson Cancer Center, proposed classifying patients into three groups that could benefit from different treatment strategies.

The first group was patients with MRD less than 0.01% who had favorable progression-free survival (PFS) despite most receiving more than 6 courses of FCR. According to the researchers, this group “could potentially stop treatment after 3 courses and be observed.”

The second group was patients with MRD between 0.01% and 1%. These patients had a favorable PFS and a high likelihood of undetectable MRD at end of therapy. This group of patients could complete an additional 3 courses of FCR and be reassessed for MRD.

The third group of patients are those with MRD > 1%. These patients had unfavorable PFS and a low likelihood of undetectable MRD at end of therapy. This group of patients is unlikely to benefit from chemoimmunotherapy, the researchers wrote.

“As such, further courses of FCR may be of limited benefit and potentially harmful; instead these patients may benefit from transitioning to salvage therapy with novel, targeted agents,” they concluded.

According to the study, patients who achieve undetectable MRD after chemoimmunotherapy have longer PFS and OS. To investigate the association between pretreatment prognostic factors and response, Thompson and colleagues conducted a study to evaluate the prognostic value of interim MRD status.

This study included 289 patients with CLL who were treated with first-line FCR. Patients underwent analysis for MRD after 3 courses of FCR and at the end of therapy. The median follow-up time was 57 months.

The overall response rate was 96%, with 64% of patients achieving complete response.

After course 3, Thomson and colleagues found 18% of patients had undetectable MRD, 40.5% of patients had MRD between 0.01% and 1%, and 41.5% had MRD greater than 1%. By the end of therapy, almost half (48%) of patients had undetectable MRD.

Undetectable MRD at the end of therapy was significantly associated with longer PFS, with a median not yet reached compared with 38 months for those who did not achieve undetectable MRD (P < .001).

A MRD level of 1% or less also predicted the likelihood of achieving undetectable MRD at end of therapy. Regarding patients with low MRD levels after course 3, the researchers found 64% achieved undetectable MRD at the end of therapy compared with only 9% of patients who had greater than 1% MRD after course 3 (P < .001). Patients with MRD of 1% or less after course 3 also had a significantly longer PFS: a median of 73 months compared with 41 months in patients whose MRD was greater than 1% (P < .001).

The researchers found re-emergence of MRD in blood in 38 of 85 evaluable patients who achieved undetectable MRD. This was detected at a median of 48 months after end of therapy. No other pretreatment characteristics were significantly associated with time to MRD re-emergence among patients who achieved undetectable MRD at the end of therapy.

“As undetectable MRD is now attainable with novel therapeutic combination strategies, we believe it will have increasing relevance as a therapeutic endpoint for the broader population of patients with CLL, particularly where the intent is to give time-limited treatment,” the researchers wrote. “Implementation of novel methods to detect MRD with greater sensitivity, such as high-throughput sequencing, may further improve the predictive accuracy of MRD assessment and refine its use as a tool for directing therapeutic decisions.”