Interim Analysis Shows Adding Lenalidomide Maintenance Therapy to Chemoimmunotherapy Prolongs Progression-Free Survival in High-Risk CLL

The combined use of genetic markers and minimal residual disease (MRD) assessment has made it easier to identify chronic lymphocytic leukemia (CLL) patients likely to have a poor outcome after receiving frontline chemoimmunotherapy, and interim results from the phase III German CLL M1 study presented at the 2016 ASH Annual Meeting suggest that these patients would benefit from adding maintenance therapy with lenalidomide to their treatment.

“This is the first study to show the benefits of lenalidomide maintenance in this patient population,” lead author Anna Maria Fink, MD, from the Center of Integrated Oncology Cologne-Bonn at the University Hospital of Cologne, said during her presentation of the results, with lenalidomide-treated patients having an 80 percent lower risk of disease progression, compared with placebo-treated patients. However, further investigation is needed to determine how lenalidomide maintenance will fit into the treatment paradigms with newer targeted therapies.

The double-blind, randomized, phase III CLL M1 study evaluated maintenance therapy with lenalidomide versus placebo in 89 CLL patients (median age = 64 years; range = 32-80 years) who achieved a partial response or better after receiving four or more cycles of frontline chemoimmunotherapy, but who were at high risk for disease progression (defined as an MRD level of ≥10-2, or MRD levels of ≥10-4 to < 10-2 with either unmutated IGHV gene status, del17p, or TP53 mutation at baseline).

Patients were randomized 2:1 to receive maintenance therapy with either lenalidomide (n=60) or placebo (n=29), starting at 5 mg daily in the first 28-day cycle and escalating in 5 mg increments until MRD negativity was achieved, with a target dose of 15 mg in the seventh cycle. If well tolerated, the study drug was administered until disease progression. After 18 cycles, all patients who still had MRD positivity continued to receive 25 mg of lenalidomide until disease progression, and patients in the placebo arm received matching placebo doses.

The patients in the study were “relatively fit,” Dr. Fink reported, with a median cumulative illness rating score of 2. The majority of patients (~60%) received a combination of rituximab with either bendamustine or fludarabine + cyclophosphamide as their frontline chemotherapy. 87 percent achieved a partial response and 9 percent achieved a complete response.

At the time of randomization, patients had the following high-risk characteristics:

  • 11.4% had del17p
  • 20.5% had TP53 mutation
  • 90.2% had unmutated IGHV gene status at baseline
  • 37% had high MRD level
  • 63% had intermediate MRD level

At the time of presentation, patients had received a median of 10 treatment cycles (range = 0-42): 11.1 cycles (range = 0.4–40.5) in the lenalidomide group and 8.3 cycles (range = 1-35) in the placebo group.

Treatment was discontinued in 27 patients on lenalidomide and 21 patients on the placebo arm, mostly due to adverse events (AEs), which were more common in the lenalidomide group (17 and 6). However, more patients in the placebo group discontinued treatment due to disease progression (4 and 13).

More patients treated with lenalidomide experienced neutropenia (30.4% vs. 3.4%), gastrointestinal disorders (55.4% vs. 27.6%), nervous system disorders (30.4% vs. 13.8%), respiratory disorders (35.7% vs. 13.8%), and skin disorders (60.7% vs. 27.6%). Rates of infection and vascular disorders, though, were similar between lenalidomide- and placebo-treated patients (50% vs. 62.1% and 14.3% vs. 17.2%, respectively). Three deaths occurred during the study period: one in the lenalidomide group (due to acute lymphocytic leukemia) and two in the placebo arm (due to progressive multifocal leukoencephalopathy and Richter syndrome).

After a median follow-up of 17.7 months, median progression-free survival was significantly longer for patients receiving lenalidomide maintenance than placebo, for both high-risk (32.3 months vs. 3.7 months) and intermediate-risk CLL patients (not reached vs. 19.4 months), and the risk of disease progression was reduced by 80 percent in patients who received lenalidomide, compared with placebo (hazard ratio = 0.198; 95% CI 0.083-0.475; p<0.0001). Overall survival, though, did not differ between the two treatment arms.

Dr. Fink noted that a number of patients who were MRD positive converted to MRD-negative status while receiving lenalidomide maintenance, but these early results will need to be confirmed in future trials.


Fink AM, Bahlo J, Sandra R, et al. Lenalidomide maintenance after front line therapy substantially prolongs progression free survival in high risk CLL: interim results of a phase 3 study (CLL M1 study of the German CLL Study Group). Abstract #229. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.