Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial

Abstract

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.

Trial registration: ClinicalTrials.gov NCT00275054.

Fig. 1. Trial flow diagram illustrating patient assessment and allocation within the CLL7 study.

AIHA autoimmune hemolytic anemia, EFS event-free survival, FCR fludarabine, cyclophosphamide, and rituximab, PFS progression-free survival, OS overall survival, W&W watch and wait.

Fig. 2. Event-free survival (EFS) and overall survival (OS) according to risk stratification/randomization (ITT).

a EFS from stratification. b OS from stratification. Hi-FCR high-risk CLL treated with early FCR, Hi-W&W high-risk CLL under observation, and Lo-W&W low-risk CLL under observation (watch and wait).

Fig. 3. Event-free survival (EFS) and overall survival (OS) according to MRD status in peripheral blood.

a EFS from MRD landmark (final response assessment/MRD evaluation). b OS from MRD landmark (final response assessment/MRD evaluation). MRD minimal residual disease. For this calculation, the MRD status at the final restaging was considered. MRD negative < 10⁻⁴; positive ≥ 10⁻⁴ detected CLL cells per leukocytes, according to MRD-flow cytometry. For MRD-results from bone marrow please refer to Supplementary Figs. 1 and 2.

Fig. 4. Time to (re)treatment (TTT) according to risk stratification/randomization and treatment status per protocol.

a Time to first treatment (TTT) in Hi- and Lo-risk patient categories, considering also Hi-FCR patients, who had withdrawn their consent for early FCR after trial inclusion. b Time to re-treatment in Hi-FCR patients, who actually underwent early FCR therapy according to the protocol (SP safety population).