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

Immunosuppressive Therapy of LGL Leukemia: Prospective Multicenter Phase II Study by the Eastern Cooperative Oncology Group (E5998)

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Free PMC article
Clinical Trial

Immunosuppressive Therapy of LGL Leukemia: Prospective Multicenter Phase II Study by the Eastern Cooperative Oncology Group (E5998)

T P Loughran Jr et al. Leukemia. .
Free PMC article

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/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.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. Survival Curves of Study Participants
Kaplan-Meier curves are presented for overall (A) and progression-free (B) survival, stratified by reason for treatment.
Figure 1
Figure 1. Survival Curves of Study Participants
Kaplan-Meier curves are presented for overall (A) and progression-free (B) survival, stratified by reason for treatment.
Figure 2
Figure 2. Heatmap of baseline sample gene expression in Methotrexate responders versus nonresponders
The top 126 genes by Z-score are displayed. Red shading indicates upregulation of mRNAs which are listed by official gene symbol at right. Samples are divided into 4 main groups from left to right, normal CD8+, normal Temra, patients with response to Methotrexate and lastly those not responding. Individual patient lanes are labeled by mutation type, type of response and trial accession number. PR = partial response, CR = complete response, NC = no change, and PROG = progression
Figure 3
Figure 3. Evidence for Increased Transcriptional Activity of the Y640F STAT3 Mutation
A) Y640F mutant greatly increased STAT3 transcriptional activity compared to STAT3 wild type and other mutants. HEK293T cells were co-transfected with Cignal STAT3 reporter harboring an SIE response element upstream of luciferase reporter and vector alone (vector), wild type STAT3 (WT), or STAT3 mutants (S614R, Y640F, D661Y or D661V). (Bottom) Western blot to detect the expression of the different STAT3 variants using human STAT3 antibody and using antibody β-actin as loading control. B) Quantitative RT-PCR indicating a reduction of the mir-223 precursor transcript in patient cells harboring the Y640F mutation. Relative expression is normalized to the mean of the Y640F sample group. C) Western blot of MYC and E2F1 in leukemic LGL and normal unactivated control CD8+ (NCD8, negative control) and activated CD8+ cells (AcCD8, positive control). Two baseline patient samples from each mutation class are di splayed. Bar graphs depicts the average level of expression of E2F1 and MYC as a proportion of GAPDH, normalized to unactivated control CD8+ samples. D) Response rates to Step 1 by mutation type as percent of total responding.

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