The pathogenesis of myelodysplastic syndromes (MDS) is primarily driven by specific genetic lesions involving the stem cell compartment, though a variety of immune pathways and mechanisms may also play a role, with autoimmune manifestations affecting the clinical history of approximately one-third of individuals with MDS. These conditions differ widely, ranging from localized to systemic disorders.

The use of immunosuppressive agents has been investigated in a small number of patients with MDS. Derangement of immune cell subsets has been observed, and T cells have been suggested for inhibiting hematopoietic precursors. Various methodological approaches have been used to explore the potential influence of immune cell subsets on MDS pathogenesis. Cytotoxic T cells and natural killer cells have been the focus of most studies, but recent research has begun to look at regulatory T cells, mesenchymal stem cells, B cells, dendritic cells, macrophages, and myeloid-derived suppressor cells.

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In a review article published in Critical Reviews in Oncology/Hematology, Claudio Fozza, MD, associate professor in the department of medical, surgical, and experimental sciences at the University of Sassari in Italy, discussed various treatment strategies for MDS, including more novel approaches and the potential use of vaccination and stem cell transplantation.

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“My point of view is that in MDS, it [is] essential to assess the potential value of immunotherapeutic approaches,” said Dr Fozza in an interview with Hematology Advisor. “Until then, only certain approaches [can be] used in clinical practice. Vaccination is not currently used, whereas stem cell transplantation can be useful for a fraction of young and well-selected patients.”

Antithymocyte Globulin and Immunomodulatory Approaches

Antithymocyte globulin (ATG) use dates back to 1988. A decade later, a phase 2 trial evaluated its use in 25 transfusion-dependent patients, 11 (44%) of whom responded and became transfusion-independent for a median of 10 months, and 3 of whom achieved complete response. Another study that included 96 patients with MDS with a median follow-up of 33.8 months found that 40 patients (42%) achieved a hematologic response, 30 (75%) of which were durable and lasted for a median of 31.5 months. Other studies found that some patients achieved red blood cell transfusion independence, while others with severe thrombocytopenia and neutropenia achieved sustained platelet counts and sustained neutrophil counts, respectively.

Thalidomide and its immunomodulatory drug (IMiD) analogues have also been used in MDS. Mechanisms of action include cytokine inhibition, modulation of cell adhesion to bone marrow stromal cells, and cytotoxic and antiangiogenic effects. The largest phase 2 study of thalidomide monotherapy evaluated 83 patients with early and advanced MDS, with 15 patients showing hematologic improvement and 10 patients becoming transfusion-independent. Other studies confirmed these results, though long-term use was limited due to an unfavorable safety profile.

The iMiD lenalidomide shares most of the immunological properties of thalidomide and has demonstrated efficacy in patients with 5q deletion, especially those at low risk. It has also shown a possible, albeit less pronounced, efficacy in patients not carrying 5q deletion, as shown by an international phase 3 randomized trial that assessed the efficacy and safety of lenalidomide in transfusion-dependent patients with International Prognostic Scoring System (IPSS) lower-risk non-del(5q) disease. Of the 239 patients enrolled, 26.9% achieved transfusion independence with a median duration of 30.9 weeks.