Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia

Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402, USA.
Blood (Impact Factor: 10.45). 10/2006; 108(6):1835-40. DOI: 10.1182/blood-2006-02-004325
Source: PubMed


A survival benefit for imatinib mesylate versus interferon-alpha therapy could not be demonstrated in the randomized study in newly diagnosed Philadelphia chromosome (Ph)-positive chronic-phase chronic myelogenous leukemia (CML) due to the high rate of crossover (90%) from interferon-alpha to imatinib mesylate within a year of study entry. We compared survival in 279 patients with newly diagnosed CML treated with imatinib mesylate at our institution (2000-2004) to 650 patients treated with interferon-alpha (1982-1997). The complete cytogenetic response rates were 87% with imatinib mesylate and 28% with interferon-alpha (P < .001). The estimated 3-year survival rates were 96% with imatinib mesylate and 81% with interferon-alpha (P < .01). Survival rates with imatinib mesylate were significantly better than with interferon-alpha within each of the CML prognostic risks groups. By multivariate analysis, imatinib mesylate therapy was identified as an independent favorable prognostic factor, after accounting for the impact of pretreatment factors (hazard ratio, 0.44; P < .01). By landmark analysis at 12 months, survival within each cytogenetic response category was similar with imatinib mesylate or interferon-alpha, suggesting that the survival benefit of imatinib mesylate (versus interferon-alpha in newly diagnosed CML) is through improving cytogenetic response.

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Available from: Farhad Ravandi
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    • "Although our study has found that patients achieving the therapeutic targets at the beginning of imatinib therapy (the 3rd or 6th month) are likely to achieve the completed therapeutic responses at the 18th month, however a minority of patients could not achieve the therapeutic target (3.4 %). In addition, the proportion of patients achieving CCyR at the 12th month in our study was lower (65 %) compared to previous randomised controlled trials in which either chronic phase patients (69 %) [27] or a higher dose (70 % of started with 800 mg daily) of imatinib (75 %) [28] were involved. "
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    ABSTRACT: Background Since the launch of imatinib, chronic myeloid leukaemia has become a chronic condition requiring costly long-term treatment. Emerging evidence from several short-term studies has raised concerns on the detrimental clinical outcomes and waste of resources associated with poor adherence to imatinib. Objective This study aims to evaluate the effects of long-term imatinib adherence on clinical treatment responses and mortality. Setting This retrospective cohort study was conducted in a medical centre in southern Taiwan. Method Chronic myeloid leukaemia patients who were prescribed for more than 1 month of imatinib were identified and their medical charts were reviewed from the first date of imatinib prescription to the last date of medical record or upon patients' death. Patients' basic characteristics, imatinib prescriptions, results of laboratory tests, episodes of imatinib-related side effects and mortality rate were recorded. Main outcome measure Participants' basic characteristics, medication possession ratio and their mortality rate; the association between the medication possession ratio and treatment responses. Results Of the 119 included patients, the mean follow-up time was 3.9 ± 2.9 patient-years and the mean medication possession ratio was 89.7 %. At the 18th month of imatinib treatment, 67.2, 54.3 and 34.5 % patients achieved complete cytogenetic, major molecular and complete molecular responses, respectively. There was a significant difference in the 4-year survival rate between the adherence (n = 87) and non-adherence (n = 32) groups (91 vs. 72 %; p = 0.0076). Logistic regression analysis revealed that imatinib adherence was the only factor that significantly influenced the 18th month complete cytogenetic response [odds ratio (OR) 11.6; 95 % confidence interval (CI) 1.7, 114.7; p = 0.0131] and major molecular response (OR 5.1; 95 % CI 1.1, 26.8; p = 0.0351). Cox regression analysis demonstrated that a medication possession ratio greater than 90 % significantly reduced the mortality risk (hazard ratio 0.1; 95 % CI 0.01, 0.60; p = 0.0118). Conclusion Chronic myeloid leukaemia patients' long-term adherence to imatinib is significantly associated with the 18th month treatment responses including the cytogenetic response, molecular response and the long-term survival rate in clinical practice.
    Full-text · Article · Jan 2014
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    • "Imatinib, which is ranked as an inferior regimen in Figure 2, continues to be recommended by the NCCN. Notably, this recommendation hinges primarily on the assertion that imatinib has shown a definitive long-term survival advantage, which is based on historical comparisons, not RCTs (the seminal IRIS trial of imatinib vs. interferon-α/low-dose cytarabine experienced a crossover rate of 90%, making long-term comparisons unreliable) [33, 34]. Because our analysis only includes RCTs, this information is not present in the visualization. "
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    ABSTRACT: Cytotoxic treatments for cancer remain highly toxic, expensive, and variably efficacious. Many chemotherapy regimens are never directly compared in randomized clinical trials (RCTs); as a result, the vast majority of guideline recommendations are ultimately derived from human expert opinion. We introduce an automated network meta-analytic approach to this clinical problem, with nodes representing regimens and edges direct comparison via RCT(s). A chemotherapy regimen network is visualized for the primary treatment of chronic myelogenous leukemia (CML). Node and edge color, size, and opacity are all utilized to provide additional information about the quality and strength of the depicted evidence. Historical versions of the network are also created. With this approach, we were able to compactly compare the results of 17 CML regimens involving RCTs of 9700 patients, representing the accumulation of 45 years of evidence. Our results closely parallel the recommendations issued by a professional guidelines organization, the National Comprehensive Cancer Network (NCCN). This approach offers a novel method for interpreting complex clinical data, with potential implications for future objective guideline development.
    Full-text · Article · Apr 2013 · Studies in health technology and informatics
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    • "The great success of imatinib has stimulated the development of a host of targeted kinase inhibitors. Although virtually every chronic-phase CML patient attains a complete hematologic remission when treated with imatinib (Kantarjian et al., 2006), drug resistance occurs at a significant rate in chronic phase patients, and is frequent among patients who are diagnosed with advanced stage disease. "
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    ABSTRACT: Resistance to molecularly targeted chemotherapy, and the development of novel agents that are active against resistant forms of target proteins create the need for a sensitive and quantitative assay to monitor drug-resistant mutations in patients to guide treatment and assess response. Here, we describe an application of the polymerase colony (polony) method to identify and quantify known point mutations in the BCR-ABL oncogene in patients with chronic myelogenous leukemia who evolve resistance to ABL kinase inhibitors. The assay can detect mutations with a sensitivity of 10(-4), quantify the burden of drug-resistant cells, and simultaneously monitor the dynamics of several coexisting mutations. As a proof of concept, we analysed blood samples from three patients undergoing therapy with ABL kinase inhibitors and found that the patients' response to therapy correlated with our molecular monitoring. We were also able to detect mutations emerging in patients long before clinical relapse. Therefore, the polony assay could be applied to a larger patient sample to assess the utility of early mutation detection in patient-specific treatment decisions. Finally, this methodology could be a valuable research tool to shed light on the natural behavior of mutations pre-existing kinase inhibitors therapy and either disappearing over time or slowly taking over.
    Full-text · Article · Feb 2008 · Oncogene
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