Fludarabine plus cyclophosphamide in Waldenström's macroglobulinemia: results in 49 patients

Tamburini, Jérôme; Lévy, Vincent; Chaleteix, Carine; Fermand, Jean Paul; Delmer, Alain; Stalniewicz, L; Morel, Pierre; Dreyfus, François; Grange, Marie‐José; Christian, Beth; Choquet, Sylvain; Leblond, Véronique

doi:10.1038/sj.leu.2403885

Cited by 70 publications

(24 citation statements)

References 26 publications

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“…However, few patients entered complete remission, responses were short-lived, and progression-free survival was poor. ORR and duration of response (DOR) improved with combinations of synergistic drugs, especially in refractory/relapsed patients [3,17]. An ORR of 96% was obtained with rituximab and fludarabine in 43 patients, 27 of whom were treatment-naive, with a median response duration of 51 months [4].…”

Section: Discussionmentioning

confidence: 99%

“…Eighty-two patients received at least one course of RFC, and 76 patients received three or more courses (median 5 courses, range [1][2][3][4][5][6]. The patients' characteristics are summarized in the Supporting Information data.…”

Section: Responsesmentioning

confidence: 99%

“…A combination of cyclophosphamide and purine analogues offers synergistic activity, as DNA breaks caused by cyclophosphamide cannot be repaired in the presence of a purine analogue [2]. Studies of the cyclophosphamide and fludarabine combination in WM patients showed an overall response rate (ORR) of 55-77%, and a median time to treatment failure of around 24 months [3]. The fludarabine and rituximab combination has also been studied in a phase II trial, with an ORR of 95.3%, a 4-year progression-free survival rate (PFS) of 67%, and a median time to progression (TTP) of 77 months [4].…”

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Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

et al. 2016

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Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Waldenstrom's macroglobulinemia (WM) is a rare B-cell malignancy characterized by the production of a monoclonal immunoglobulin (IgM) by welldifferentiated plasmacytic lymphocytes. Therapy is currently reserved for patients with constitutional symptoms, bone marrow or peripheral lymphoid organ involvement, and complications due to the monoclonal IgM component [1]. There is no consensus treatment strategy, and most clinical trials in WM have so far consisted of small phase II studies with widely differing inclusion and response criteria. Classically used chemotherapeutic agents consist of alkylating agents (chlorambucil, cyclophosphamide), purine analogues (fludarabine, 2-chlorodeoxyadenosine or 2CDA), a proteasome inhibitor (bortezomib) and bendamustine, used either alone or, more often, combined with immunotherapy (principally rituximab). A combination of cyclophosphamide and purine analogues offers synergistic activity, as DNA breaks caused by cyclophosphamide cannot be repaired in the presence of a purine analogue [2]. Studies of the cyclophosphamide and fludarabine combination in WM patients showed an overall response rate (ORR) of 55-77%, and a median time to treatment failure of around 24 months [3]. The fludarabine and rituximab combination has also been studied in a phase II trial, with an ORR of 95.3%, a 4-year progression-free survival rate (PFS) of 67%, and a median time to progression (TTP) of 77 months [4]. Rituximab, fludarabine, and cyclophosphamide combination therapy (RFC) yields a high response rate in patients with chronic lymphocytic leukemia (CLL), both as first-line treatment and after relapse [5,6], and is more effective than the FC combination in untreated CLL patients [7]. Until no...

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Section: Discussionmentioning

confidence: 99%

Section: Responsesmentioning

confidence: 99%

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confidence: 99%

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Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

et al. 2016

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“…[50][51][52][53][54] Because alkylating agents and nucleoside analogues have been shown to be effective, combinations of these agents have been tested, and response rates of 58% to 88% have been observed. [55][56][57] The addition of rituximab to these agents has been well tolerated with little additional toxicity and appears to further increase the response rate. 58-60 Recent studies using the proteasome inhibitor bortezomib in combination with rituximab have found this combination to be effective.…”

Section: Choice Of Initial Therapymentioning

confidence: 99%

Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines

Ansell

Kyle

Reeder

et al. 2010

Mayo Clinic Proceedings

149

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“…8 In a phase II study, analyzing 49 patients, the combination of fludarabine and cyclophosphamide achieved an OR of 77.6% and a median time to treatment failure (TTF) of 27 months. 9 All these data underline that conventional chemotherapy is effective in LPL and WM, but to a limited extent. CD20 is strongly expressed on most of the cells in LPL and WM forming a rationale to incorporate the anti-CD20 antibody rituximab into the therapy of this disease.…”

Section: Introductionmentioning

confidence: 99%

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

et al. 2008

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Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n ¼ 34) or CHOP (n ¼ 30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P ¼ 0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P ¼ 0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P ¼ 0.0033) and in the WM subgroup (P ¼ 0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.

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Fludarabine plus cyclophosphamide in Waldenström's macroglobulinemia: results in 49 patients

Cited by 70 publications

References 26 publications

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

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