Lenalidomide Maintenance Improves PFS in High-Risk CLL

Anna Maria Fink, MD

Lenalidomide as maintenance following first-line immunochemotherapy substantially improves progression-free survival (PFS) in the treatment of patients with high-risk chronic lymphocytic leukemia (CLL), according to interim analysis of the phase III CLLM1 study. Too few overall deaths have occurred in the trial to determine the effect of lenalidomide maintenance on overall survival (OS) in this patient population, said Anna Maria Fink, MD, at the 2016 ASH Annual Meeting.

After a median follow-up of 17.5 months, lenalidomide maintenance led to a relative risk reduction of 80% in PFS. “The Data Safety Monitoring Board (DSMB)-assessed results of this interim analysis as statistically significant, robust, and reliable in favor of lenalidomide,” said Fink, from the department of Internal Medicine, University Hospital Cologne, Germany. “They recommended the unblinding of this study and the continuation of lenalidomide treatment.”

CLLM1 is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in which the efficacy and safety of oral lenalidomide maintenance therapy is being compared to that of placebo maintenance therapy in patients with CLL with a high risk of progression.

Patients were classified as having a high risk for progression if they had achieved at least a partial response and had minimal residual disease (MRD) levels ≥ 10^-2 or MRD levels ≥10^-4 to < 10^-2 combined with either an unmutated IGHV gene status, del(17p), or TP53 mutation after first-line therapy. Patients with these features were previously found to have much lower PFS than CLL patients without these features, providing the rationale for CLLM1.

Of the 468 patients screened, 379 were excluded, with 347 excluded for being low risk (MRD-negative). The investigators therefore randomized 89 patients from 5 countries to lenalidomide maintenance or placebo in a 2:1 ratio.

Lenalidomide was administered according to the following schedule: 5 mg daily on days 1—28 of the first 28-day cycle. If the 5 mg dose level was well tolerated, the dose was raised to 10 mg/day on days 1–28 of cycle 2–6; further escalations starting with the seventh cycle and up to the 12th cycle to 15 mg/day was permitted. If patients still had MRD levels ≥10^-4 in peripheral blood after 12 cycles, and if the previous dosage was well-tolerated, escalation up to 20 mg/day was permitted starting with cycle 13. If after 18 cycles of treatment, MRD levels were still ≥ 10^-4, a maximum of 25 mg/day of lenalidomide was permitted, starting with the 19th cycle.

First-line immunotherapy, administered outside of the trial, consisted of either fludarabine, cyclophosphamide, and rituximab (FCR); bendamustine and rituximab (BR); or fludarabine and cyclophosphamide at the treating physician’s discretion. About 60% of patients in each arm received BR as first-line treatment and about 40% received FCR.

At data cut-off, the median number of cycles that patients received was 11 in the lenalidomide arm and 8 in the placebo arm. Some 78.6% of patients in the lenalidomide arm could receive at least 1 day of treatment with 10 mg.

Treatment was discontinued in 42.9% of patients on lenalidomide and in 72.4% of patients in the placebo arm. Adverse events were the main reason for discontinuation in patients who received lenolidomide (32.1%); disease progression was the main reason for discontinuation in patients receiving placebo (44.8%). Toxicity was modest with lenalidomide, said Fink. Infections, gastrointestinal disorders, skin disorders, and blood and lymphatic disorders were the most common adverse events in the lenalidomide-treated patients, each occurring in >60% of patients.

The hazard ration for PFS was 0.148 (95% CI 0.063-0.347; P < .00001) in favor of lenalidomide, corresponding to an 80% improvement. The median PFS was not yet reached in the lenalidomide arm and was 13.3 months in the placebo arm.

When PFS was analyzed by MRD level at randomization, patients with a medium MRD level had a better PFS than those with high MRD levels, “but lenalidomide was effective in both of the strata, leading to a hazard ratio of less than 0.2 in both of these strata,” said Fink.

There were only 3 deaths so far in the study, so no trend in OS could be detected. Analysis of OS will be conducted at the study conclusion in 2021. There were no conversions to MRD negativity in the placebo arm compared with about 8% in the lenalidomide arm.

Fink AM, Bahlo J, Sandra R, et al. Lenalidomide maintenance after frontline 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). Paper presented at: American Society of Hematology 58^th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 229.

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Median age of the patients was 64 years and their median Cumulative Illness Rating Scale score was 2 (range, 0-6). In the lenalidomide and placebo groups, 13.5% and 7.7%, respectively, had a 17p deletion; 17.9% and 25.9%, respectively, had a TP53 mutation, and about 90% in each group had an unmutated IGHV gene status at baseline. At randomization, 37% of patients had a high MRD level (≥ 10^-2) and 63% had an intermediate MRD level (≥10^-4 to < 10^-2).