Other immunomodulatory approaches are being evaluated as well. One study looking at sirolimus in 19 patients found that 3 achieved either a major or a minor hematologic response, but 25 mg temsirolimus per week was associated with considerable toxicity and no benefit in elderly patients with MDS. In another study, transfusion independence was achieved by 3 of 9 low-risk patients with MDS treated with mycophenolate mofetil. Tumor growth factor-beta receptor 1 kinase and IRAK1, an immune-modulating kinase, have been identified as potential therapeutic targets within in vitro studies.

Of note, programmed death 1 (PD-1) signaling may be involved in MDS pathogenesis and may play a role in resistance mechanisms to hypomethylating agents, “thus suggesting its possible therapeutic targeting in order to overcome such a resistance,” Dr Fozza stated in the review.

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Vaccination is a relatively novel treatment approach, and research has been limited. The Wilms tumor gene product 1 (WT1)-peptide vaccination, which has been more widely assessed in patients with acute myeloid leukemia, was evaluated in a cohort of WT1-expressing patients with MDS that included 2 patients with refractory anemia with excess of blasts (RAEB). Both treated patients demonstrated a major neutrophil response that was detectable within 4 weeks of treatment initiation and continued until disease progression. In addition to the clinical results, patients showed a decline in WT1 mRNA levels and an increase of WT1-tetramer T cells in both peripheral blood and bone marrow.

More recently, 2 patients with high-risk MDS were vaccinated with a mixture of peptides derived from the WT1 protein, and 1 patient achieved a prolonged decrease in transfusion dependence. In another cohort of patients, a high-dose RHAMM-R3 peptide vaccination induced specific immunological responses, reduced leukemic blasts, and improved peripheral blood counts.

Nonmyeloablative Hematopoietic Stem Cell Transplant

Reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT) has been evaluated in MDS, with varying results. Despite this, HSCT remains the only curative approach available for these patients. One retrospective study included 43 patients with MDS or AML arising from MDS. The 2-year overall survival, disease-free survival, relapse rate, and transplant-related mortality were 53%, 51%, 16%, and 35%, respectively; grade 2 to 4 acute graft-versus-host disease was observed in 63% of the cohort. Although no significant survival difference was observed between sibling donor and matched unrelated donor HSCT, the relapse rate was higher among sibling donor recipients (38% vs 7%).

Another study with 128 patients, 40 of whom received azacitidine prior to transplant, showed a 3-year overall survival of 53%, relapse-free survival of 37%, cumulative incidence of relapse of 35%, and nonrelapse mortality of 20% for the azacitidine cohort. For patients who didn’t receive azacitidine, these values were 53%, 42%, 36%, and 23%, respectively.

“Considering a good fraction of subjects with MDS are still candidates for therapeutic approaches that are able to modify the disease history only marginally, as well as the unequivocal role of immune mechanisms in the pathogenesis of these disorders, we suggest that a strategy based on retuning the immune system [should] be further exploited in this clinical setting,” Dr Fozza concluded.


1.     Fozza C. Retuning the immune system in myelodysplastic syndromes: from immunomodulatory approaches to vaccination strategies and non myeloablative hemopoietic cell transplant [published online November 16, 2018]. Crit Rev Oncol Hemat. doi:10.1016/j.critrevonc.2018.11.001