Positive Impact of T-Cell Clonal Expansion On Overall Survival in Patients with High-Risk Myelodysplastic Syndromes.

Suppression of clonal T-cells has been linked to immunosuppressive therapy response in patients with lower-risk MDS and with other forms of autoimmune bone marrow failure suggesting that T-cell clonal expansion is pathogenic to bone marrow hematopoiesis. It is possible, however, that clonal T-cells expanding in response to leukemia-associated antigens (LAA) may ultimately suppress tumor progression through immunosurveillance. Our group previously identified clonal T-cell expansion in 50% of MDS patients (n=52) compared to 5% in age matched control (n=20) (results published by Epling-Burnette et al, Leukemia 21:659, 2007). There was no statistically significant association between clonal T cell expansion and WHO subtype, IPSS, karyotype, transfusion dependency, age or gender in a cross-sectional analysis. Identification of the prognostic importance of clonal T-cell expansion is an important decision point concerning immunosuppressive therapies. We report here on overall survival for both lower and higher-risk MDS patients based on clonal T-cell expansion status.

The original study enrolled 52 patients diagnosed with MDS and 20 healthy volunteers. Peripheral mononuclear cells were isolated and clonal T cells were identified through analysis of the complementarity determining region (CDR)-3 of the T-cell receptor (TCR) using multiplex TCR-Vβ(CDR3) PCR on genomic DNA and by flow-cytometric analysis of Vβ expanded families. In this study, we retrospectively reviewed records of the 52 patients identified previously after obtaining IRB approval. We compared outcome of patients with evidence of clonal T-cell expansion in the peripheral blood to patients without clonal T-cell expansion. Data collected included demographic characteristics, WHO subtype, cytopenias at diagnosis, karyotype, and IPSS, subsequent therapies, disease progression, and survival. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). Kaplan–Meier curves were used for estimates of median overall survival.

Long-term follow up data were available on 48 of the original 52 MDS patients and 50% had evidence of clonal T-cell expansion (n=24). RCMD was the commonest WHO subtype among both groups (n=24, 50%) and more patients were lower-risk based on IPSS (n=32, 67%). No difference in median overall survival (OS) was observed among the two groups based on the status of clonal T-cell expansion (55.8 mo with clonal T-cell expansion and 58.3 mo without clonal T-cell expansion, P-value 0.76. Patients were then stratified by IPSS into low/int-1 (lower risk) and int-2/high (higher risk) groups for subset analysis. In patients with a low/int-1 IPSS risk classification, the trend in median OS (median OS 79 mo in the positive group n=14; and 76 mo in the negative cohort n=18) was similar in both groups and consistent with previously published data from the International MDS risk analysis workshop (IMRAW/IPSS) for patients with low/int-1 IPSS risk classification. Interestingly, patients with clonal T-cell expansion in the int-2/high (higher risk) IPSS MDS group (n=10) had a median OS of 30 mo compared to 12 month in the same IPSS risk group with no clonal T-cell expansion (n=6). Therefore, the presence of clonal T-cells in higher risk MDS patients was associated with an improved outcome compared to reported median OS in higher risk IPPS MDS patients in the IMRAW database. Out of the 48 patients 14 received azacitidine; only two of the 6 patients with clonal T cell expansion (33%) had a response to azacitidine compared to 5 out of 8 patients (63%) without clonal T cell expansion.

The exact etiology of the clonal T-cell expansion is not known but may be autoimmune, homeostatic or antigen-driven. Improved survival in higher-risk patients with clonal T-cell expansion suggests a distinct pathophysiological mechanism. T-cell response may be generated to LAA providing immuneosurveillance that may be an important mechanism to slow disease progression. Furthermore, certain immunological signatures may be used as predictive tools for response to treatment. This study suggests that clonal T-cell expansion may be an important molecular determinant associate of improved survival outcome and a prospective larger cohort is warranted to confirm these observations.

No relevant conflicts of interest to declare.