First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group.

Hallek, Michael; Fingerle-Rowson, Guenter; Fink, Anna‐Maria; Busch, Raymonde; Mayer, Jiřı́; Hensel, Manfred; Hopfinger, Georg; Heß, Georg; Gruenhagen, Ulrich von; Bergmann, M.; Catalano, John; Zinzano, Pier Luigi; Cappio, F. Caligaris; Seymour, John F.; Berrébi, Alain; Jaeger, Ulrich; Cazin, Bruno; Trněný, Marek; Westermann, Anne; Wendtner, Clemens‐Martin; Eichhorst, Barbara; Staib, Peter; Böettcher, Sebastian; Ritgen, Matthias; Mendila, Myriam; Kneba, Michael; Doehner, Hartmut; Stilgenbauer, Stephan; Fischer, Kirsten

doi:10.1182/blood.v114.22.535.535

Cited by 56 publications

(26 citation statements)

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“…The data from the present multicentre retrospective study on 109 patients confirm and extend the experience acquired in the treatment of relapsed CLL patients with bendamustine (Kath et al, 2001;Aivado et al, 2002;Bergmann et al, 2005;Lissitchkov et al, 2006). Currently, the combination of rituximab, fludarabine and cyclophosphamide (RFC) is considered to be the most active immunochemotherapy, producing the best results as first-line treatment in terms of CR, PFS and even OS (Hallek et al, 2009). RFC is also considered to be among the most active regimens for the treatment of relapsed patients (Wierda et al, 2005).…”

Section: Discussionsupporting

confidence: 79%

Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study

et al. 2011

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Summary To retrospectively assess the efficacy of bendamustine alone and with rituximab (R–B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39–85). Forty‐three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1–8). Twenty‐two patients received bendamustine alone and 87 patients received R–B (median B dosage: 100 mg/m2 per day, range 90–130 mg/m2 per day). The overall response rate was 69·6% (complete response 28·6%; partial response 41%), and was significantly higher in patients treated with R–B (P = 0·014) and in those responsive to the previous treatment (P = 0·04). After a median follow‐up of 7·9 months (range 1–148), the median progression‐free survival was 16 months and the median duration of response was 13 months. Median overall survival (OS) was 16·8 months for the whole cohort; patients not responding to the treatment had a significantly worse outcome than those who attained a response (P = 0·0001). In multivariate analysis, only resistant disease status at start of bendamustine treatment (HR 3·2, 95% CI 1·4–7·3, P = 0·006) had an independent prognostic value for OS. Toxicity was manageable and mostly haematological. In conclusion, in our experience R–B was an effective and well‐tolerated treatment for relapsed/refractory CLL patients, producing a remarkable high CR rate and mild toxicity.

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Section: Discussionsupporting

confidence: 79%

Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study

et al. 2011

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“…Although the treatments given in the LRF CLL4 trial have now been superseded by the introduction of chemo‐immunotherapy combinations, the question of the efficacy of oral fludarabine compared with iv remains highly relevant. Fludarabine is still a major component of most regimens for the treatment of CLL (notably FC plus rituximab, which has been administered iv thus far12, 13) and the ability to deliver the drug as an oral therapy offers practical and cost advantages. Overall, there was no evidence of any clinically relevant difference in trial endpoints for patients treated on LRF CLL4 which could be attributed to the route of administration of fludarabine.…”

Section: Discussionmentioning

confidence: 99%

A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial

Dearden

Richards

Else

et al. 2010

Cancer

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BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m2 oral dose with a 25 mg/m2 intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total of 777 patients were randomized from 1999‐2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression‐free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87‐1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received. Cancer 2011. © 2010 American Cancer Society.

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“…45 In response to these promising results, the GCLLSG compared FCR to FC in a multicenter, international phase III randomized trial. 5 In a recent update (after a median observation time of 37.7 months), the group reported a higher OR rate with FCR compared to FC (95.1% vs 88.4%) and more CRs (44.1% vs 21.8%). FCR vs FC also produced a longer median PFS (51.8 months vs 32.8 months) and higher OS at 37.7 months (84.1% vs 79%) (P = .01), though the superiority in OS was observed only in patients with Binet stage A and B disease.…”

Section: Rituximabmentioning

confidence: 93%

“…4 More effective combination regimens, such as fludarabine, cyclophosphamide, and rituximab (Rituxan ® , Genentech, Inc, South San Francisco, CA) (FCR), have recently been shown to prolong progression-free survival (PFS) and overall survival (OS), thereby changing the treatment paradigm to one with a goal of complete elimination of the disease in patients who are both younger and older but physically fit. 5 Therefore, more aggressive management may be warranted for patients who can tolerate the additional toxicities.…”

Section: Introductionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia: Putting New Treatment Options into Perspective

Pinilla‐Ibarz

McQuary

2010

Cancer Control

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Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell malignancy that afflicts mainly older individuals. Since many patients are diagnosed in the earliest stages, the course of the disease may be indolent and asymptomatic, requiring no therapy. For those who are diagnosed in advanced stages or whose disease becomes symptomatic, treatment is indicated. Advances in identifying prognostic factors, such as cytogenetics, IgHV mutational status, CD38, TP53, and ZAP-70, are helping physicians better predict who is more likely to have progressive disease and thus needs more frequent monitoring. Some of these prognostic factors are also helping to guide therapy choices as they can predict response to treatment and/or duration of response. Recent advances in treatment options have moved beyond traditional management with alkylating agents and purine analogs into regimens combining these two chemotherapy classes with monoclonal antibodies targeting CD20. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has become the most effective therapy option to date for CLL. Compared with fludarabine and cyclophosphamide, FCR has shown higher complete response rates and longer progression-free survival. Bendamustine, a unique alkylating agent with purine analog properties, has recently been approved by the FDA for treatment of CLL and provides a new alternative to existing therapies. Initial trials combining bendamustine with rituximab are showing promise for both untreated and relapsed/refractory disease. Other agents recently approved and/or being tested, such as ofatumumab, flavopiridol, and lenalidomide, are demonstrating activity in the relapsed setting.

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Cited by 56 publications

References 0 publications

Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study

Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study

A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial

Chronic Lymphocytic Leukemia: Putting New Treatment Options into Perspective

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