Abstract Background: MDS is a neoplasm that primarily affects older adults and can lead to bone marrow failure, and cytopenias. T-LGLL is an indolent T-cell lymphoma associated with autoimmune disorders caused in some cases by somatic mutations in STAT3/5. In rare instances, MDS can co-present with T-LGLL leading to the overlap diagnosis of MDS/T-LGLL. There are currently no guidelines on how to treat patients (pts) who present with both conditions. In our study, we examine the rare subset of pts who present with MDS/T-LGLL overlap to identify distinct features of these malignancies that can facilitate treatment strategies. Methods: A retrospective analysis was conducted on pts with either T-LGLL or MDS/LGLL overlap. Single-cell RNA and single cell T-cell receptor (TCR) sequencing was performed on bone marrow samples from 5 pts (T-LGL n = 1, MDS n = 2, MDS/T-LGL n = 1, and healthy control n = 1) to characterize immune cell populations. Bulk RNA sequencing was conducted on T-LGL cells from bone marrow samples from 6 pts to assess gene expression (MDS/T-LGLL n = 3 and T-LGL n = 3). Plasma cytokine levels were measured using ELISA on 9 pts to evaluate immune signaling profiles (MDS n = 3, T-LGL n = 3, MDS/T-LGL n = 3). Results: We identified 8 pts with T-LGLL and 8 patients with MDS/T-LGLL from our institution. We found MDS/T-LGLL pts to have higher rates of neutropenia with an average ANC of 0.72 cells/uL compared to 1.54 cells/uL in T-LGLL pts. MDS/T-LGLL pts also presented with a lower frequency of STAT3/5 mutations (12.5% vs 43%), and more infection-related deaths (57% vs 0%). Frequency of autoimmune disorders was similar among both groups. Of note, 2 of the 8 pts with MDS/T-LGLL had an MDS diagnosis at least one year prior to the diagnosis of T-LGLL. These 2 patients presented with no autoimmune conditions, no STAT3/5 mutations, and did not respond to T-LGLL-directed therapy. This observation prompted further analysis to determine whether pts who developed MDS followed by T-LGLL represent a distinct subset. Single cell and bulk RNA sequencing analyses comparing CD8+ T cells from pts with de novo T-LGLL vs MDS/T-LGLL, suggested a unique mechanism of cytotoxic CD8+ T-cell dysregulation in MDS/T-LGLL pts, distinct from pts with T-LGLL alone. Gene expression analysis showed higher expression of T-cell exhaustion markers in pts who first presented with MDS followed by T-LGLL, compared to patients with the single diagnosis of T-LGLL. We also found that expression of LAG3,TIGIT, andCTLA4 was higher in MDS/T-LGLL samples than in T-LGLL alone, while TOX and GZMB were lower. This suggests a more dysfunctional CD8 T-cell phenotype in the MDS/T-LGLL group. Functional analyses further support impaired cytotoxic signaling in the MDS/T-LGLL disease, with reduced Granzyme B and other T-cell activation cytokines in plasma, along with decreased T-cell degranulation assays. We further conducted single cell TCR VDJ sequencing to understand the differences in repertoire diversity between these groups. Interestingly, a patient who first developed MDS followed by MDS/T-LGLL had a significantly lower number of unique clones, compared to patients who had the single diagnosis of T-LGLL or patients who had first developed T-LGLL and later MDS. This finding suggests T-cell clonal expansions in MDS/T-LGLL could be associated with MDS specific antigens in some patients, although further work is needed to determine this. Conclusions: Together, our findings suggest that MDS/T-LGLL can present with higher grades of neutropenia and develop more infectious complications. Interestingly, we also found a subset of MDS/T-LGLL pts who first present with MDS, followed by T-LGLL. Patient samples from this population represent a distinct immunobiological entity, characterized by expanded and dysfunctional cytotoxic T cells, and altered activation states. Based on the observation that one of these patients had low number of unique TCR clones, we suspect MDS can potentially accelerate T-LGLL through neoantigen presentation, contributing to the immune dysfunction and clonal expansion seen in the combined diagnosis. Clinically, these patients did not respond to T-LGLL directed therapy, suggesting a different therapeutic strategy may be warranted. Ultimately, a deeper understanding of the MDS/T-LGLL overlap could inform new therapeutic strategies for this rare but clinically significant patient population.
Pereira et al. (Mon,) studied this question.