Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 27, Issue 4, Pages 491-497Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2008.16.4459
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Funding
- National Institutes of Health [R01 CA67823]
- Lymphoma Foundation
- Michael Sweig Foundation
- John and Cynthia Reed Foundation
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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 (F3C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F -> C -> R). Patients and Methods 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 IgVH 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 F3C regimen (P = .10). Conclusion Sequential therapy with F -> C -> R yields improvement in quality of response, with many patients achieving a PCR-negative state.
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