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.
Highlights
Clinical observation without therapy—defined as “watch and wait” (W&W)—has been the gold standard for the management of early-stage chronic lymphocytic leukemia (CLL)
Between 2005 and 2010, a total of 824 patients were registered for the CLL7 study, 423 in 69 German CLL study group (GCLLSG) centers in Germany (51.3%), Austria, and Switzerland, and 401 (48.7%) in 25 centers of the French Cooperative Group on CLL (FCGCLL) in France
There was an imbalance in the prevalence of elevated thymidine kinase (TK), short lymphocyte doubling time (LDT), male sex, and del(11q) between the two high-risk cohorts
Summary
Clinical observation without therapy—defined as “watch and wait” (W&W)—has been the gold standard for the management of early-stage chronic lymphocytic leukemia (CLL). A reasonable subset of patients with CLL experience an indolent disease course with neither compromising morbidity nor an elevated risk of premature death caused by the leukemia. Such patients have a life expectancy comparable with the normal population, and there is no justification to expose these cases to any potentially harmful antileukemic therapy [5,6,7].
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