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Sequential gene expression profiling during treatment for identification of predictive markers and novel therapeutic targets in chronic lymphocytic leukemia

Leukemia volume 24, pages 2122–2127 (2010)Cite this article

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The clinical course of chronic lymphocytic leukemia (CLL) is variable and depends on disease stage, prognostic factors, age and comorbidity.1, 2 Complete remission (CR) or partial remissions are initially obtained in most fit patients treated with combinations of fludarabine (F), cyclophosphamide (C) and rituximab (R) (FC or FCR).3 Unfortunately, all patients will eventually relapse. There is an unmet need for biological predictors of individual drug response to facilitate correct treatment decisions early on. So far, gene expression profiling (GEP) in vivo in CLL was mainly used in a cross-sectional approach by studying patient samples before treatment.4 We applied a sequential GEP (sGEP) approach to investigate the gene expression signature of CD19+ selected CLL cells before and after treatment in vivo. This was complemented by protein analysis as well as by functional in vitro analysis of selected targets. The goals of this study were to (1) define molecular signatures associated with good or poor response to treatment; (2) understand differences in gene expression profiles after treatment with rituximab with FC or FC alone; (3) define changes in expression signatures shortly after treatment in responding and resistant CLL cases; (4) identify novel targets to overcome resistance. A number of genes that were up- or downregulated in responding patients were identified. We also provide a list of genes that were upregulated in CLL cells in association with insufficient clinical response. This library may serve to design drug combinations or sequences of administration to avoid or overcome resistance.

A total of 20 patients with CLL diagnosed by standard criteria were enrolled in this study between 2004 and 2007. Eight patients were recruited within the CLL-8 study of German CLL Study Group. Sixteen patients received first-line and four second-line treatment. All patients were in Binet stage B (N=10) or C (N=10). Characteristics of all study patients are given briefly in Table 1 and Supplementary Table 1. Treatment was planned for six cycles with a 28-day interval according to standard FC or FCR protocols.2, 3 Peripheral blood samples were collected during the first cycle of therapy immediately before treatment, 1 day after rituximab administration and 1 day after FC (FCR group) or 1 day after FC (FC group). The study protocol was approved by the local ethics committee (no. 495/2003 and 11/2005). The type of clinical response after 3 months allowed classifying the patients into good responders (RE) including CR or partial response (PR) or nonresponders (NR) comprising stable disease (SD) or progressive disease (PD). Overall, 9 patients had adequate responses (9 PR) and 11 patients had inadequate responses (9 SD, 2 PD). We noted some imbalances between responders and nonresponders regarding mutational status (4 vs 8 IgVH unmutated) as well as poor-risk cytogenetics (11q deletions in 1 vs 5 cases). There were four responders in the FC and five in the FCR group with more UM patients in the FC nonresponder group compared with responders (4 UM vs 1 UM). This was less pronounced for FCR patients (4 UM in nonresponders vs 3 UM in responders) suggesting that mutational status is not always directly correlated with response.

Table 1 Summary of patient's characteristic
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Acknowledgements

We thank Eva-Maria Muzik for the technical assistance and microarray analysis. This project was supported by grants from the Austrian Ministry of Education, Science and Culture through the project Gen-AU-Child (GZ 200.136/1–VI/1/2005) (UJ), the ‘Cancer Research Initiative’ of the Medical University of Vienna (MS), the Austrian Society of Hematology and Oncology (RH), Medizinisch-Wissenschaftlichen Fonds des Bürgermeisters der Bundeshauptstadt Wien (BMG2522) (MS), Austrian National Bank Jubiläums Fonds (ÖNB11051) (MS), ‘Fellinger Krebsforschung’ Society (MS) and an unrestricted research grant by Roche, Austria.

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Authors and Affiliations

  1. Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    M Shehata, D Demirtas, S Schnabl, M Hilgarth, R Hubmann, K Eigenberger, D Heintel, E Porpaczy, K Vanura, A Hauswirth, J D Schwarzmeier, A Gaiger & U Jäger

  2. Karl Landsteiner Institute for Cytokine and Tumour Microenvironment, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    M Shehata, J D Schwarzmeier & U Jäger

  3. Department of Internal Medicine I, Ludwig Boltzmann-Cluster Oncology, Medical University of Vienna, Vienna, Austria

    M Shehata, R Hubmann & U Jäger

  4. Department of Internal Medicine I, Comprehensive Cancer Center (CCC)/Drug & Target Screening Unit (DTSU), Medical University of Vienna, Vienna, Austria

    M Shehata & U Jäger

  5. Department of Medical Genetics, Medical University of Vienna, Vienna, Austria

    C Fonatsch

  6. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria

    I Schwarzinger & M Bilban

  7. Third Medical Department, Hanusch-Krankenhaus, Vienna, Austria

    G Hopfinger

  8. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    S Stilgenbauer

  9. German CLL Study Group, Germany

    S Stilgenbauer, M Hallek & U Jäger

  10. Department of Internal Medicine I, University of Cologne, Cologne, Germany

    M Hallek

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  1. M Shehata
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Correspondence to U Jäger.

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Shehata, M., Demirtas, D., Schnabl, S. et al. Sequential gene expression profiling during treatment for identification of predictive markers and novel therapeutic targets in chronic lymphocytic leukemia. Leukemia 24, 2122–2127 (2010). https://doi.org/10.1038/leu.2010.220

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