Individualized-Dose Lenalidomide-Based Regimen a Possible Frontline Treatment for Advanced CLL

A triplet regimen consisting of chlorambucil and rituximab (Rituxan) in combination with an individualized dose of lenalidomide (Revlimid) can potentially be used as a frontline treatment for patients with advanced chronic lymphocytic leukemia (CLL) who are older or unfit for standard treatment with fludarabine, cyclophosphamide, and rituximab (FCR).

By adopting an individualized-dose approach to treatment with the immunomodulatory drug, the investigators were able to lessen toxicity concerns from treatment with single-agent lenalidomide that have been previously seen in patients with CLL. The combination regimen demonstrated an overall response rate (ORR) of 83% and an acceptable safety profile in a Dutch phase I/II trial.

“Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile and less frequent occurrence of tumor lysis syndrome and tumor flare reactions,” the study authors, led by Arnon P. Kater, MD, PhD, wrote in their report recently published inHaematologica.

The investigators conducted a phase I/II study of the triplet combination in patients with advanced CLL at 26 centers in the Netherlands.

Eligible patients were aged 65 to 80 or were between 18 and 64 with a Cumulative Illness Rating Scale ≥7, Binet C stage, or Binat A or B with active disease. 

Twelve patients were enrolled in phase I, which focused on determining the maximum-tolerated dose (MTD) and the recommended phase II dose level for chlorambucil in the combination. Patients were treated with the combination including chlorambucil at 1 of 2 dose levels, either 7 mg/m²or 10 mg/m². The recommended phase II dose level for chlorambucil was determined at 7 mg/m²on days 1 through 7.

In phase II, patients were treated with 6 cycles of 28 days each of chlorambucil at the recommended phase II dose plus rituximab on day 1 at 375 mg/m²for cycle 1 and 500 mg/m²for cycles 2 through 6. Lenalidomide was given at 2.5 mg on days 9 through 28 of cycle 1, 5 mg or the MTD on days 1 through 28 of cycle 2, and 10 mg or the MTD on days 1 through 28 of cycles 3 through 6. This was considered the induction-I portion of phase II. In the induction-II portion, lenalidomide was administered at 10 mg or the MTD for days 1 through 28 for 6 additional cycles.

Fifty-seven patients were enrolled in phase II, and 53 patients were evaluable for the intention-to-treat (ITT) analysis as 4 patients were eventually found to have small lymphocytic leukemia.

The median patient age was 71 years (range, 60-80) and a majority of patients (42%) had Rai stage III disease. Of 39 patients with evaluable mutational status, 20 had mutatedIGHV.

After a median follow-up of 27 months, the median progression-free survival (PFS) was 49 months. At 2 years, the PFS rate was 58% and was 54% at 3 years.

The PFS for the 36 patients who started the induction-II phase was 41 months and the 2-year PFS rate was 56%.

The median overall survival (OS) was not yet reached at the time of data cutoff. At 2 years, the OS rate was 98% and was 95% at 3 years.

The ORR was 83% (95% CI, 72%-92%) in the ITT analysis. After the end of induction II, the ORR was 93% (95% CI, 79%-98%) including 14% complete responses and 79% partial responses. Any additional 2 patients (5%) had stable disease, and only 1 patient had progressive disease. As of data cutoff, no deaths had occurred among the patients who started induction II.

Median event-free survival (EFS) was 49 months and the EFS rate was 53% at 3 years.

Flow-based minimal residual disease (MRD) analysis of peripheral blood was performed in 41 patients and 4 (8%) achieved MRD negativity after induction I and 2 (4%) after induction II.

Of the 53 patients in the ITT analysis, 47 completed the induction-I portion and 36 completed induction II. Eleven patients discontinued in the induction-I portion due to excessive toxicity in 8 patients, refusal in 2, and progression in 1. An additional 6 patients discontinued in the induction-II phase with 5 due to excessive toxicity and 1 due to refusal.

Treatment was completed per protocol in 36 patients (68%). During induction I, the median dose of lenalidomide was 86.7% and 99.7% during induction II.

Regarding toxicity, no tumor lysis syndrome was observed. Tumor flair reaction was noted in 5 patients, 1 case of which was grade 3. Six patients developed a secondary malignancy, all but 1 was a localized skin cancer, the other was a solid tumor.

“Although our study has shown that adverse events and deaths can be reduced by using individualized dose schedules, intensive monitoring is required,” the investigators wrote.

The most common hematologic adverse event (AE) was grade 3/4 neutropenia in 73% during induction I and in 64% during induction II. Grade 3/4 thrombocytopenia was also observed in 15% in the induction-I phase and in 17% during induction II.

Nonhematologic grade 3/4 AEs occurred in 40% during induction I and 19% during induction II, most commonly including infections and infestations, general administration site conditions, and skin and subcutaneous tissue disorders.

“Based on the findings of this study and on lenalidomide’s unique mechanisms of action, there might be a role for this drug or for the newer immunomodulatory treatments either in combination with novel agents, or in patients who are not eligible for novel therapies such as ibrutinib,” the study authors concluded.

Reference:

Kater AP, van Oers MHJ, van Norden Y, et al; HOVON CLL study group. Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia.Haematologica.2019;104(1):147-154. doi: 10.3324/haematol.2018.193854.