ASH 2022: Novel Approaches in MDS

During the 64th ASH Annual Meeting, Dr. Verma outlined the various inflammatory mediators that are elevated in MDS, the TGF-beta pathways as well as inflammatory cascades triggered by spliceosome mutations in MDS, and the role of inflammation in the development of immature cells and low blood counts in MDS. 

Clonal hematopoiesis and inflammation

When a mutation in a hematopoietic (immature) stem cell (such TET2, DNMT3A, or ASXL1) occurs, the mutant cell exhibits abnormalities of key SMOCs (supramolecular organizing centers) that control natural immune and inflammatory pathways. In contrast, the inflammatory environment suppresses normal immature stem cells. Over time, the mutant immature stem and progenitor cells acquire additional mutations that may lead to MDS.  At the MDS stage, the mutant cells overwhelm the normal healthy cells and lead to overall impaired blood cell formation.

Inflammation and MDS 

Autoimmune and inflammatory conditions are seen in up to 25% of patients with MDS. A wide range of autoimmune and inflammatory conditions have been reported in association with MDS and can range from limited symptoms to more intense diseases affecting multiple organs. 

Abnormal cytokines (process of one cell dividing into two), chemokines (proteins made up of immune and other cells), and growth factor levels in MDS. Of the cytokines that are noted to be altered amongst various studies, tumor necrosis factor-α (TNFα), interferon –Υ (IFNγ), transforming growth factor β (TGFβ), interleukin-6 (IL-6), and IL-8, and overexpression of inflammasome activation S100A8/9 are the most consistently noted to be over-expressed inflammatory pathways contribute to clonal hematopoiesis (the process of an immature cell making more cells with the same genetic mutations).

Many of the immunologic dysregulations, or upsets, in MDS can also promote autoimmunity and inflammation and chronic inflammatory conditions like infections. Increasing age, HIV, tobacco use, chemotherapy, and prior radiation are also precursors of MDS and inflammation. 

Through data coming from clinical trial research, their appears to be a relationship between inflammation, natural immune signaling, and MDS. The new approach presented by Dr. Verma with this information, would be to find specific drugs that aim to attack the signaling pathways that promote inflammation and clonal mutations (mutations that are present in all MDS cells).  

Dr. Verma mentioned a phase 1/2a study of the IRAK4 inhibitor, Emavusertib (CA-4948) in High-Risk-MDS and Regular-Risk-AML, and he emphasized the importance of targeting pathways that lead to inflammation and innate immunity to improve the patient's outcome, looking forward to new targeted therapies and clinical trials.

References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711159/
2. https://pubmed.ncbi.nlm.nih.gov/27337745/
3. https://rupress.org/jem/article/218/7/e20201544/212382/Innate-immune-pathways-and-inflammation-in