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Abstract
Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. Patients with higher risk MDS have dismal outcomes and treatment options are very limited. Aside from allogeneic hematopoietic cell transplantation, the only potentially curative treatment, DNA methyltransferase inhibitors (DNMTIs) are the only intervention that prolongs overall survival in patients with higher risk MDS. The clinical use of DNMTIs in MDS was one of the earliest successful attempts at epigenetic reprogramming of cancer. In this review, we discuss the clinical use of DNMTIs in MDS highlighting the current challenges and controversies and future directions of research needed to explore the full therapeutic potential of these agents.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Evidence suggests that aberrant methylation patterns play a key role in the pathogenesis of myelodysplastic syndromes (MDS).
Treatment with azacitidine and decitabine leads to durable responses especially in higher risk MDS. Aside from allogeneic hematopoietic stem cell transplant (allo-HSCT), treatment with azacitidine is the only intervention that improves overall survival in higher risk MDS patients.
Responses to azacitidine and decitabine can be delayed so treatment should not be aborted before at least 6 months of treatment. In responders, treatment should continue indefinitely.
More data are needed to assess the efficacy and safety in lower risk MDS.
Cytoreduction before transplant is usually recommended in patients with >10% blast. Cytoreductive therapy with DNA methyltransferase inhibitor (DNMTI) seems to be equivalent to intensive chemotherapy.
Patients who are candidates for alloHSCT should undergo the procedure as soon as possible and not wait till DNMTI failure occurs as outcomes of alloHSCT are worse after DNMTI failure.
Several combination strategies with DNMTI are being investigated but so far none seems to be significantly more effective than DNMTI.
Several biopredictors to DNMTI treatment have been identified, however, the available data are not compelling enough to alter treatment decisions.