Originally published as JCO Early Release 10.1200/JCO.2008.16.4459 on December 15 2008

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Sequential Therapy With Fludarabine, High-Dose Cyclophosphamide, and Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia Produces High-Quality Responses: Molecular Remissions Predict for Durable Complete Responses

From the Memorial Sloan-Kettering Cancer Center, New York, NY.

Corresponding author: Mark A. Weiss, MD, Associate Attending, Leukemia Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: weissm{at}mskcc.org.

Purpose Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (FC). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (FCR).

Patients and Methods Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m² on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m² administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m² for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV_H genes.

Results There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior FC regimen (P = .10).

Conclusion Sequential therapy with FCR yields improvement in quality of response, with many patients achieving a PCR-negative state.

Supported in part by Grant No. R01 CA67823 from the National Institutes of Health and grants from the Lymphoma Foundation, the Michael Sweig Foundation, and the John and Cynthia Reed Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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