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

Leukemia. 2015 Apr;29(4):886-94. doi: 10.1038/leu.2014.298. Epub 2014 Sep 13.


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/m(2) 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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anemia / complications
  • Anemia / drug therapy*
  • Anemia / genetics
  • Anemia / mortality
  • Cyclophosphamide / therapeutic use
  • Drug Monitoring
  • Female
  • Finland
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • International Cooperation
  • Leukemia, Large Granular Lymphocytic / complications
  • Leukemia, Large Granular Lymphocytic / drug therapy*
  • Leukemia, Large Granular Lymphocytic / genetics
  • Leukemia, Large Granular Lymphocytic / mortality
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Mutation
  • Neutropenia / complications
  • Neutropenia / drug therapy*
  • Neutropenia / genetics
  • Neutropenia / mortality
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Survival Analysis
  • Transcriptome
  • United States


  • Immunosuppressive Agents
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Cyclophosphamide
  • Methotrexate