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

• Published in: Journal of clinical oncology Vol. 27; no. 4; pp. 491 - 497
• Main Authors: LAMANNA, Nicole, JURCIC, Joseph G, ZELENETZ, Andrew D, WEISS, Mark A, NOY, Ariela, MASLAK, Peter, GENCARELLI, Alison N, PANAGEAS, Katherine S, HEANEY, Mark L, BRENTJENS, Renier J, GOLDE, David W, SCHEINBERG, David A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01.02.2009
• Subjects: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents - administration & dosage; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Biological and medical sciences; Cyclophosphamide - administration & dosage; Drug Administration Schedule; Female; Flow Cytometry; Follow-Up Studies; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Original Reports; Polymerase Chain Reaction; Remission Induction; Rituximab; Tumors; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Antineoplastic agent; Nucleotide analog; Monoclonal antibody; Cancerology; Sequential; Lymphoproliferative syndrome; Immunotherapy; Quality; Remission; High dose; Human; Purine nucleotide; Rituximab; Malignant hemopathy; Alkylating agent; Oxazaphosphinane derivatives; Cyclophosphamide; Chronic lymphocytic leukemia; Fludarabine; Treatment; Antimetabolic; Nitrogen mustard; Fluorine Organic compounds; Predictive factor; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.16.4459

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 (F-->C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F-->C-->R). Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m(2) on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m(2) administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m(2) 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. 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 F-->C regimen (P = .10). Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.