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 (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). 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 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 F-->C regimen (P = .10). CONCLUSION: Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.
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 (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). 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 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 F-->C regimen (P = .10). CONCLUSION: Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.
Authors: Christine Mayr; Michael R Speicher; David M Kofler; Raymund Buhmann; John Strehl; Raymonde Busch; Michael Hallek; Clemens-Martin Wendtner Journal: Blood Date: 2005-09-22 Impact factor: 22.113
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Authors: H Döhner; S Stilgenbauer; A Benner; E Leupolt; A Kröber; L Bullinger; K Döhner; M Bentz; P Lichter Journal: N Engl J Med Date: 2000-12-28 Impact factor: 91.245
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Authors: S Johnson; A G Smith; H Löffler; E Osby; G Juliusson; B Emmerich; P J Wyld; W Hiddemann Journal: Lancet Date: 1996-05-25 Impact factor: 79.321
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Authors: John C Byrd; Bercedis L Peterson; Vicki A Morrison; Kathleen Park; Robert Jacobson; Eva Hoke; James W Vardiman; Kanti Rai; Charles A Schiffer; Richard A Larson Journal: Blood Date: 2002-07-05 Impact factor: 22.113
Authors: John F Seymour; Shuo Ma; Danielle M Brander; Michael Y Choi; Jacqueline Barrientos; Matthew S Davids; Mary Ann Anderson; Anne W Beaven; Steven T Rosen; Constantine S Tam; Betty Prine; Suresh K Agarwal; Wijith Munasinghe; Ming Zhu; L Leanne Lash; Monali Desai; Elisa Cerri; Maria Verdugo; Su Young Kim; Rod A Humerickhouse; Gary B Gordon; Thomas J Kipps; Andrew W Roberts Journal: Lancet Oncol Date: 2017-01-13 Impact factor: 41.316