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  • Original Article
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Immunology

Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)

Leukemia volume 29, pages 886–894 (2015)Cite this article

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Abstract

Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m2 orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.

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Acknowledgements

We acknowledge Rob Brucklacher of Penn State Hershey Functional Genomics for performing microarrays. We also thank Arjan van Adrichem for the creation of the Y640F STAT3 plasmid. Su-Fern Tan and Alex Wendling provided assistance with the conversion of figures. This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA73590, CA11083, CA14548, CA13650, CA17145, CA78724, CA90633, CA94872 and CA133525 from the NCI, NIH and the DHHS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.

Author Contributions

TL designed and was principal investigator of the study, determined clinical responses of participants and wrote the manuscript. LZ and VW statistically analyzed clinical response and laboratory correlates and wrote the manuscript. TO designed and performed serum correlate experiments, designed and analyzed microarray experiments, designed confirmatory experiments and wrote the manuscript. DZ designed and performed STAT3 activation assays. HR and SM designed and performed experiments measuring STAT3 mutations in the patient cohort and contributed to the manuscript. ZH designed and performed experiments measuring molecules downstream of STAT3. JB, ML, AE and MT conceptualized and administered the clinical trial and provided critical review of the manuscript.

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Author notes

  1. T P Loughran: Formerly at Moffitt Cancer Center Tampa, FL, USA.

  2. T L Olson: Formerly at Penn State Cancer Institute, Hershey, PA, USA.

  3. A M Evens: Formerly at Department of Medicine, Hematology/Oncology, The University of Massachusetts Medical School, Worcester, MA, USA.

  4. M S Tallman: Formerly at Northwestern University School of Medicine, Chicago, IL, USA.

Authors and Affiliations

  1. University of Virginia Cancer Center Charlottesville, VA, USA

    T P Loughran Jr, T L Olson, D Zhang & Z Hasanali

  2. Dana Farber Cancer Institute, Boston, MA, USA

    L Zickl & V Wang

  3. Hematology Research Unit, Helsinki University Central Hospital, Helsinki, Finland

    H L M Rajala & S Mustjoki

  4. Department of Medicine, Hematology/Oncology, University of Rochester Cancer Center, Rochester, NY, USA

    J M Bennett

  5. Department of Medicine, Hematology/Oncology, Ireland Cancer Center, Cleveland, OH, USA

    H M Lazarus

  6. Department of Hematology, Mayo Clinic, Rochester, MN, USA

    M R Litzow

  7. Tufts Cancer Center, Boston, MA, USA

    A M Evens

  8. Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    M S Tallman

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  1. T P Loughran Jr
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  2. L Zickl
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Corresponding author

Correspondence to T P Loughran Jr.

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Loughran, T., Zickl, L., Olson, T. et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia 29, 886–894 (2015). https://doi.org/10.1038/leu.2014.298

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