MRD Effective as Surrogate Endpoint in CLL?

December 12, 2018

A patient’s minimal residual disease status may serve as a surrogate marker for outcome in clinical trials of chronic lymphocytic leukemia in patients with comorbidities.

A patient’s minimal residual disease (MRD) status may serve as a surrogate marker for outcome in clinical trials of chronic lymphocytic leukemia (CLL), according to a recent study that showed MRD status was independently associated with progression-free (PFS) and overall survival (OS) in patients with comorbidities.

“There is now increasing evidence to support the use of MRD as a surrogate endpoint for long-term outcome in clinical trials,” wrote Anton W. Langerak, of Erasmus University Medical Center, Netherlands, and colleagues in Blood. “While most of this evidence comes from studies carried out in young, fit patients, our data shows that MRD retains its prognostic significance in a patient population that is generally older, less fit, and treated with less intense treatment regimens.”

According to the study, most patients with CLL are older and have one or more comorbidities making them ineligible for intensive chemotherapy regimens. However, the CLL11 trial established that obinutuzumab plus chlorambucil (G-Clb) as a standard of care for previously untreated CLL in patients with comorbidities. The trial showed a greater benefit to G-Clb than rituximab plus chlorambucil (R-Clb).

Here, Langerak and colleagues used data from CLL to look at the effect of these two treatment regimens on MRD levels and whether MRD assessment had any prognostic value.

The CLL11 trial was a randomized, three-arm, phase III study comparing safety and efficacy of G-Clb and R-Clb vs Clb alone (stage 1), and G-Clb vs R-Clb (Stage 2) in patients with untreated CLL and comorbidities. For this analysis, the researchers considered only the 663 patients from stage 2.

The patients were randomly assigned 1:2:2 to Clb alone, G-Clb, or R-Clb. MRD was analyzed in peripheral blood and bone marrow, and patients were classified as MRD-positive, MRD-intermediate, and MRD-undetectable.

Using peripheral blood, 19% of patients were MRD-undetectable, 27.8%, MRD-intermediate, and 53.2% were MRD-positive. Patients with undetectable MRD had a median PFS of 56.4 months compared with 23.9 months for MRD-intermediate patients (Hazard Ratio [HR], 2.65; 95% CI, 1.91–3.69; P < .001) and 13.9 months for MRD-positive patients (HR, 6.53; 95% CI, 4.78–8.92; P < .001).

MRD was also associated with OS rates. The median OS was longer for patients with undetectable MRD compared with intermediate MRD (HR, 1.43; 95% CI, 0.91–2.26) and significantly longer compared with MRD-positive patients (HR, 2.24; 95% CI, 1.49–3.37; P < .001).

An undetectable MRD was more common in patients treated with G-Clb compared with those assigned R-Clb (35.8% vs 3.3%, P < .001). Additionally, patients with MRD-undetectable had numerically longer PFS when treated with G-Clb than in those treated with R-Clb (57.3 vs 35.6 months). According to the researchers, this difference “may suggest preferential clearing of peripheral blood in the G-Clb arm however, patient numbers in the R-Clb arm are too low to allow any firm conclusions to be drawn.”

No treatment differences were observed for patients with MRD-intermediate or positive patients.

Multivariate analysis showed that MRD-positivity and G-Clb treatment were independent prognostic factors for progression-free survival in peripheral blood. MRD-positivity was also an independent prognostic factor for OS (P < .003).