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      The long‐term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years

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          Summary

          With 10+ years follow‐up in the Leukaemia Research Fund (LRF) CLL4 trial, we report the effect of salvage therapy, and the clinical/biological features of the 10‐year survivors treated for chronic lymphocytic leukaemia ( CLL). Overall survival ( OS) was similar in the three randomized arms. With fludarabine‐plus‐cyclophosphamide ( FC), progression‐free survival ( PFS) was significantly longer ( P < 0·0001), but OS after progression significantly shorter, than in the chlorambucil or fludarabine arms ( P < 0·0001). 614/777 patients progressed; 524 received second‐line and 260 third‐line therapy, with significantly better complete remission ( CR) rates compared to first‐line in the chlorambucil arm (7% vs. 13% after second‐, 18% after third‐line), but worse in the FC arm (38% vs. 15% after both second and third‐line). OS 10 years after progression was better after a second‐line CR versus a partial response (36% vs. 16%) and better with FC‐based second‐line therapy (including rituximab in 20%) or a stem cell transplant (28%) versus all other treatments (10%, P < 0·0001). The 176 (24%) 10‐year survivors tended to be aged <70 years, with a “good risk” prognostic profile, stage A‐progressive, achieving at least one CR, with a first‐line PFS >3 years and receiving ≤2 lines of treatment. In conclusion, clinical/biological features and salvage treatments both influence the long‐term outcome. Second‐line therapies that induce a CR can improve OS in CLL patients.

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          Most cited references 14

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          Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.

          Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%. We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC. The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin. FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).
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            Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial.

             T Zenz,  M Hallek,  M Mendila (2012)
            To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups. Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
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              Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia.

              Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL. This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276). After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life. R-FC significantly improved the outcome of patients with previously treated CLL.
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                Author and article information

                Journal
                Br J Haematol
                Br. J. Haematol
                10.1111/(ISSN)1365-2141
                BJH
                British Journal of Haematology
                John Wiley and Sons Inc. (Hoboken )
                0007-1048
                1365-2141
                12 October 2015
                January 2016
                : 172
                : 2 ( doiID: 10.1111/bjh.2016.172.issue-2 )
                : 228-237
                Affiliations
                [ 1 ] Division of Molecular PathologyThe Institute of Cancer Research LondonUK
                [ 2 ]Clinical Trial Service Unit OxfordUK
                [ 3 ] Department of Molecular PathologyRoyal Bournemouth Hospital BournemouthUK
                Author notes
                [* ] Correspondence: Daniel Catovsky, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.

                Email: daniel.catovsky@ 123456icr.ac.uk

                Article
                BJH13824
                10.1111/bjh.13824
                4832371
                26457986
                © 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 10
                Product
                Funding
                Funded by: Leukaemia and Lymphoma Research
                Funded by: Cancer Research UK
                Funded by: Arbib Foundation
                Funded by: Schering Health Care (UK)
                Funded by: Schering AG (Germany)
                Categories
                Research Paper
                Haematological Malignancy
                Custom metadata
                2.0
                bjh13824
                January 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:22.04.2016

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