Functional T Cell Array Reveals Pre-Treatment Expanded Terminal Effector Memory Response Is Associated with Lenalidomide Failure in Non-Del(5q) Myelodysplastic Syndrome.

Abstract 1759

Poster Board I-785

Lenalidomide (LEN) is a thalidomide derivative with proven efficacy for the treatment of patients with myelodysplastic syndrome (MDS). High rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)] produced the first FDA-approved karyotype-specific treatment for this disease. Transfusion-independence rates of approximately 25% have been reported previously for patients with non-[del(5q)] and efficacy in this population has been linked to the promotion of erythroid differentiation. Because impaired erythroid differentiation in lower-risk MDS may occur through several pathophysiological mechanisms, the identification of additional factors with predictive value for both response and failure to LEN are needed to optimize success of treatment. In addition to affecting erythroid differentiation, LEN has well-known potential for immune modulation and generates highly potent effector T cell responses in vitro and in vivo by potentiating T cell receptor signaling. Immune deregulation mediated by autoreactive effector T cells has been linked to impaired erythropoiesis and granulopoiesis in a distinct subset of MDS patients raising the question of whether LEN impacts the disease process in this subset of patients. To understand the relationship between T cell deregulation and LEN response, we conducted a pilot study of 13 low/INT-1-risk non-del (5q) MDS patients (7 responders and 6 non-responders) treated with LEN and determined 23 covariates related to functional T cell response measured prior to treatment and then correlated to treatment outcome. Of these 23 covariates, multiple T cell immune parameters were analyzed but were not associated with response including interferon-g (IFNg) production by CD4+ T cells (p=0.9) and CD8+ T cells (p=0.27), Tumor Necrosis Factor (TNF)-a production by CD4+ T cells (p=1.0) and CD8+ T cells (p=0.8), TCR-associated proliferation within the CD4+ (p=1.0) and CD8+ (p=0.4) compartment, CD4/CD8 ratio (p=0.3), percentage of CD4+ (p=0.5) and CD8+ (p=0.5) T lymphocytes, and the percentage of naïve and three different types of memory CD4+ T cells. Analysis was performed using two-group comparison statistical tests (two-sample t-test and Wilcoxon rank sum test) to compare responders (R) vs non-responders (NR). Only one factor was independently linked to LEN response. Results showed that a higher percentage of CD8 T cells (mean 56% in NR vs 32% in R) with a Terminal Effector Memory [TEM]) phenotype (CD45RA+/CD62L-) was associated with LEN failure (p=0.02). This population of T cells occurs at a low frequency in healthy individuals but can be induced to differentiate in vitro under constant exposure to long-term antigen and cytokine stimulation. We have shown previously that CD8+ TEM T cells are expanded in patients with impaired myelopoiesis due to immune dysregulation in Large Granular Lymphocyte (LGL) leukemia. In conclusion, these results suggest that CD8+ terminal effector memory expansion may be linked to immune deregulation in MDS and represents an important biomarker with negative predictive importance for LEN response in non-del(5q) low-risk MDS.