A network meta-analysis of therapies for previously untreated chronic lymphocytic leukemia

University of Washington, Department of Pharmacy, Box 357630, Seattle, WA 98195-7630, USA. Electronic address: .
Cancer Treatment Reviews (Impact Factor: 7.59). 03/2012; 38(8):1004-11. DOI: 10.1016/j.ctrv.2012.02.006
Source: PubMed


Several therapy options are available for symptomatic, treatment-naïve chronic lymphocytic leukemia (CLL). Many of these therapies have been compared against chlorambucil, but have not been directly compared against each other. There is currently no agreed upon standard therapeutic regimen for treatment-naïve CLL.
We performed a systematic literature review to identify randomized controlled trials (RCTs) published prior to November 2011 of therapies for previously untreated CLL. We conducted a network meta-analysis using fixed and random effect statistical models to estimate differences between shape and scale parameters of progression-free survival (PFS) curves for each competing therapy. We used the parameter estimates and a Weibull distribution to project mean PFS for each therapy option.
Five RCTs were included in our comparison network. Overall, patients were younger (59-65years), had good performance status based on the Eastern Cooperative Oncology Group scale (ECOG 0-1), and earlier stage disease (Rai 0-II or Binet A or B). The combination regimen fludarabine with cyclophosphamide and rituximab (FCR) was estimated to yield mean PFS of 76months (95% CrI: 60, 91), FC 60months (46, 73), fludarabine 38months (27, 49), alemtuzumab 24months (15, 32), and chlorambucil 23months (15, 32).
Our results suggest that FCR has relatively higher potential of preventing disease progression in younger, healthier, treatment-naïve CLL patients and should be considered an optimal initial treatment strategy for this patient population. However, because estimates are based on model simulation, additional studies of FCR are necessary to clinically validate its therapeutic potential.

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    • "fludarabine vs. alkylator-based regimen, purine analogues vs. alkylating agents, etc.) that were tested head-to-head in the source RCTs. In 2012, Cheng et al. [12] reported results of the network meta-analysis using a Bayesian analytic framework applied to the survival data obtained from RCTs [13] [14] [15] [16] [17] identified during the systematic literature review in order to simultaneously analyze therapies that previously have not been directly compared in terms of PFS. In this meta-analysis two hazard models were considered and the Weibull model was demonstrated to fit the data taken from the RCTs more closely than log–logistic one. "
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    ABSTRACT: Background: A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL). Methods: We compared available therapies for treatment-naïve, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis. Results: In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90months for fludarabine, RClb, chlorambucil and GClb, respectively. Conclusions: Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS.
    No preview · Article · Feb 2015 · Cancer Treatment Reviews
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    ABSTRACT: The combination of two chemotherapeutic drugs, fludarabine and cyclophosphamide (FC), with the rituximab (RTX) - FCR - in the treatment of chronic lymphocyte leukemia (CLL) is associated with a high complete remission rate. In recent years FCR has become the first-line choice for CLL patients under 65 year of age. Delayed leucopenia has been described in rituximab-treated CLL patients. However among reported cases, the late onset and progressive lymphopenia was not noticed in individuals with CLL. The present study reports the case of a 53-year-old Caucasian man who developed prolonged progressive lymphopenia after 18 weeks RTX treatment-free period. Irrespective of no drug intake, in 13-week follow up, the amount of B lymphocytes as well as the serum levels of IgG decreased (93.22% and 20% reduction, respectively). Progressive neutropenia with hypogammaglobulinemia has constantly intensified leading to the necessity of gamma globulin supplementation and administration of granulocyte colony-stimulating factor (G-CSF). The present findings suggests that FCR therapy in some individuals may lead to the induction of persistent alteration of the cellular and humoral immunity.
    No preview · Article · Jan 2012 · Central-European Journal of Immunology
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identification of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efficacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.
    Full-text · Article · Dec 2013 · Oncotarget
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