Results of a Phase II of Low-Dose Fludarabine and Cyclophosphamide Combined with Standard Dose Rituximab (FCR-LITE) in Elderly, Untreated Patients with Chronic Lymphocytic Leukemia (CLL): The Israeli CLL Study Group Experience

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients.

Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission.

When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy.

Patients and Methods

We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m²/day together with IV cyclophosphamide 150 mg/m²/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m², and at 500 mg/m² on day 1 of cycles 2-6.

Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up.

All statistical tests were two sided. P<0.05 was considered as statistically significant.

Results

Forty patients treated with FCR-LITE were included in the efficacy analysis.

The median age of the entire cohort was 72.7 years (range, 65.0 to 85.0), and 69% were male. The mean number of treatment cycles was 5.1 (range 1-6).

The overall response rate was 67.5% (95% CI, 50.9%-81.4%); 17 patients (42.5%) achieved CR and 10 (25.0%) PR.

Median PFS was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period.

Reduced cumulative doses of FCR and fewer courses of treatment were both associated with lower CR rate.

Hematological toxicities were the most common side effects encountered; grade-3/4 neutropenia occurred in twenty (47.6%) patients, only six (14.3%) developed neutropenic fever. Positive direct antiglobulin test (DAT), was seen in 11 patients but none of them developed autoimmune hemolytic anemia (AIHA) during treatment; two patients (4.8%) progressed to Richter's transformation and two (4.8%) had second malignancies (lung and metastatic colon carcinoma).

Conclusion

FCR-LITE is effective and safe for treating elderly patients with therapy-naïve CLL. It has the advantage of being both time and cost effective. In an era of novel agents, it can still be considered as suitable frontline treatment for fit elderly patients with CLL.

This research was supported by roche pharmaceuticals

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