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

Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 12/2008; 27(4):491-7. DOI: 10.1200/JCO.2008.16.4459
Source: PubMed


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.

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Available from: Mark Heaney, Mar 26, 2014
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    • "The efficacy of the FCR combination as well as the possible associated toxicities led to the investigation of two different regimens in which the three drugs were combined at different dosages or were administered sequentially with the aim of reducing toxicity while preserving efficacy.81,82 "
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    ABSTRACT: The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin's lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia.
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    • "Grade 3 or 4 neutropenia occurred in 32 patients (89%), major infectious complications occurred in only 5 patients (14%). Although this regimen seems to be safe and efficacious, only a randomized study could establish whether this schedule is superior in terms of response and toxicity to FCR.22 "
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    • "Interestingly, since rituximab plus FC represents the standard treatment for B-CLL, clinical studies compared the conventional regimen to rituximab plus low-dose FC (i.e., FCR-Lite) or to sequential FC and rituximab [49], since these alternative regimens are expected to be associated with less grade 3 or 4 neutropenia than the conventional R-FC regimen [5, 50]. "
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