Anemia Associated with Increased IL-6 and IL-8 Levels Predicts for Worse Progression-Free Survival in T-Cell and NK-Cell Large Granular Lymphocyte (LGL) Leukemia but Is Improved by Treatment with Cyclophosphamide
Authors: Portell Craig A. , Visconte Valeria , Clemente Michael J. , Afable Manuel G. , Tabarroki Ali , Traina Fabiola , Liu Yang , Hamilton Betty K. , Jarez Andres , Bupathi Manoj , Horwitz Leonard J. , Lichtin Alan E. , Advani Anjali , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Tiu Ramon V. 
Published: October 2019

Abstract
Abstract 1261
LGL leukemia is a rare bone marrow failure disorder characterized by a clonal expansion of terminally differentiated T- or NK-cells with large cytoplasmic granules. Cytopenias of one or multiple lineages are the dominant phenotype, though lymphocytosis without cytopenias can also be present. Goals of therapy are minimizing cytopenias. Currently used immunosuppressive and chemotherapeutic agents have produced variable clinical responses. Predictors of response to therapy and overall outcomes have not been well studied. We reviewed 92 LGL patients (pts, T-LGL=79, NK-LGL=13) seen at Cleveland Clinic from January 2000 to July 2012 treated with various therapeutic agents.
Overall (OS) and Progression-Free (PFS) Survival and Time to Next Treatment (TTNT) were estimated using the Kaplan-Meier method. The first three treatments for LGL pts were evaluated with TTNT; observation was not considered a treatment for this analysis. Risk factors for PFS and OS after initial treatment (including those who were never treated) were identified using Cox proportional hazard analysis. Clinical factors evaluated at time of diagnosis include age, sex, neutropenia (absolute neutrophil count ≤1000 per μL), anemia (hemoglobin ≤10gm/dL or transfusion requirement), lymphocytosis (absolute lymphocyte count >4000 per μL), lymphopenia (absolute lymphocyte count ≤1000 per μL), thrombocytopenia (platelet count ≤100 per μL), transfusion dependence (any red-cell transfusion requirement around time of diagnosis), history of B-cell dyscrasia and history of an autoimmune disease. Clinicopathologic risk factors included type of LGL leukemia (T- vs. NK-cell), detection of a monoclonal protein, number of Vβ clones measured by flow cytometry, and T-cell clonality by T-cell receptor (TCR)-γ rearrangement. P values of ≤0.05 were considered statistically significant. The median age of the cohort was 63 years (range: 16–85). 61% were male. Treatments (n=129) included cyclophosphamide (n=31), cyclosporine (n=33), methotrexate (n=25), alemtuzumab (n=12), chemotherapy (n=7), others (n=21), and supportive care or observation (n=28). Median TTNT was 18 months (range <1 to 122 months).
Pts with neutropenia had worse PFS (6 vs 72 months; p≤0.0001) as did pts with anemia (17 vs 77 months; p=0.07) compared to pts without these cytopenias. Pts with a monoclonal T-cell population via TCR-γ rearrangement also had a worse PFS compared to those with biclonal or oligoclonal T-cell population (11 vs 46 months vs not reached [NR]; p=0.04). Multivariable analyses supported these findings for PFS (anemia: HR=2.2, CI 1.10–4.67, p=0.03; T cell clonality: HR= 2.43, CI 1.16–5.48, p=0.02; neutropenia: HR=3.92, CI 1.87–8.78, p=0.0002).
To provide biologic insight into the pathogenesis of anemia and its associated prognostic outcome in LGL leukemia, we performed cytokine analysis on plasma samples using a Multi-Analyte ELISArray Kit for human inflammatory cytokines that interrogates a total of 12 cytokines including IL-1A, IL-1B, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17-A, IFN-γ, TNF-α, and GM-CSF. We found increased levels of IL-6 and IL-8 in LGL pts with isolated anemia compared to pts without cytopenias. Full analysis with available samples from our cohort is ongoing. IL-6 has been associated with poor outcomes in some bone marrow syndromes.
Cyclophosphamide produced the most durable TTNT compared to other treatments (36 vs. 15 months, p=0.04), particularly in those with anemia, (36 vs. 8 months, p=0.007) though its effects were negligible in pts with neutropenia (9 vs. 11 months, p=0.38).
In summary, LGL is an indolent disorder with a long natural history and frequent episodes of progression. We found that anemia associated with increased IL-6 and IL-8 levels and monoclonal T-cell population predicts for worse PFS together with neutropenia. Treatment with cyclophosphamide is associated with better TTNT particularly in the presence of anemia. Cyclophosphamide is a reasonable treatment option for pts with LGL leukemia presenting with anemia.

Disclosures:
Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.